CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease

Marius Strioga; Vita Pasukoniene; Dainius Characiejus

doi:10.1111/j.1365-2567.2011.03470.x

. 2011 Sep;134(1):17–32. doi: 10.1111/j.1365-2567.2011.03470.x

CD8⁺ CD28⁻ and CD8⁺ CD57⁺ T cells and their role in health and disease

Marius Strioga ¹, Vita Pasukoniene ¹, Dainius Characiejus ²

PMCID: PMC3173691 PMID: 21711350

Abstract

Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8⁺ T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8⁺CD28⁻ or CD8⁺CD57⁺ T lymphocytes. There is growing evidence that the CD8⁺CD28⁻ (CD8⁺CD57⁺) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8⁺CD28⁻ (CD8⁺CD57⁺) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8⁺CD28⁻ (CD8⁺CD57⁺) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8⁺CD28⁻ (CD8⁺CD57⁺) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8⁺CD28⁻ (CD8⁺CD57⁺) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8⁺CD28⁻ (CD8⁺CD57⁺) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8⁺CD28⁻ (CD8⁺CD57⁺) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.

Keywords: CD8⁺ CD28⁻ T cells, CD8⁺ CD57⁺ T cells, immunosenescence

Introduction

CD8⁺ T cells are pivotal for the recognition and clearance of cells infected by intracellular pathogens¹ and are the key players in antitumor immune response.² They receive activation signal when their T-cell receptor (TCR) recognizes MHC-I-bound peptide antigen, presented on the surface of professional antigen-presenting cells (pAPCs), namely dendritic cells (DCs) and macrophages/monocytes.³ However, this interaction is low-affinity and requires a large number of TCR ‘hits’ so in the majority of cases the stimulation via TCR alone is unable to sustain optimal activation of naive and memory CD8⁺ T cells.⁴^–⁶ Therefore a second (co-stimulatory) signal is generally indispensable for their full activation and survival.⁶ The best defined (but not the sole) co-stimulus is provided by the interaction of CD28 (on the surface of the T cell) and CD86 or CD80 (on the surface of the pAPC).³^,⁴

The delivery of appropriate activation signals to naive CD8⁺ T cells leads to their proliferation and concomitant differentiation into cytotoxic T lymphocytes (CTL), which die by apoptosis after elaborating their effector functions, and memory CD8⁺ T cells (both central and effector), which are generated in much smaller quantities and are retained for fighting potential subsequent exposure to the same antigens, eliciting a more rapid and aggressive response.⁷^,⁸ Stimulation of central memory CD8⁺ T cells by their cognate antigen leads to the formation of CTL (also effector memory T cells) and next-generation central memory CD8⁺ T cells, whereas stimulation of effector memory T cells leads to rapid realization of their effector functions, as well as their proliferation.⁸ Under persistent antigenic stimulation several such activation cycles occur and with each repetitive stimulation/proliferation round CD28 expression is progressively and irreversibly down-regulated on the surface of CD8⁺ T cells, eventually leading to the accumulation of highly antigen experienced CD8⁺ CD28⁻ T cells with critically shortened telomeres.³^,⁵

Initially, the replicative history of CD8⁺ T cells was defined by the loss of CD28; later it was found that with the decrease of CD28, the expression of CD57 increases.⁹^,¹⁰ CD57 (HNK-1, Leu-7, L-2) is a terminally sulphated carbohydrate determinant (glycoepitope) found on various surface glycoproteins, proteoglycans and glycolipids on subsets of natural killer (NK) cells (its expression in the haematopoietic lineage was first detected on these cells), T cells, also on vertebrate neuronal cells and in the eye.³^,¹¹^,¹²

The loss of CD28 and gain of CD57 expression is also observed on CD4⁺ T cells during chronic immune activation,¹³^,¹⁴ but an oligoclonal CD4⁺ CD28⁻ (CD4⁺ CD57⁺) T-cell population accumulates at significantly lower rates and exists at substantially lower frequencies in human peripheral blood.⁵^,¹³^,¹⁵^,¹⁶ Nevertheless they may show a significant increase in some autoimmune diseases (e.g. rheumatoid arthritis, Wegeners's granulomatosis, multiple sclerosis¹¹^,¹⁵), also they may play a role in the vascular inflammation in atherosclerotic disease that may eventually lead to plaque instability, which may cause acute coronary syndromes and stroke.¹⁵^,¹⁷ Moreover, late-differentiated CD4⁺ CD28⁻ T cells can acquire perforin expression and lytic capacity.¹⁸^.

The loss of CD28 and gain of CD57 expression on T cells during persistent immune stimulation is a definite immunological characteristic of humans and non-human primates but not of mice.⁵^,¹⁵ Although immunosuppressive CD8⁺ CD28⁻ T cells are identified in mice,¹⁹^,²⁰ they are not the result of chronic antigenic stimulation, do not express CD57 and represent a distinct subset of naturally occuring CD8⁺ T cells with an intrinsic propensity to not express CD28.²⁰ Age-associated clonal expansion of CD8⁺ T lymphocytes with strong proliferative capacity and ability to secrete interferon-γ (IFN-γ) is observed in mice, but these T cells tend to have elevated levels of CD28 expression.²¹

Several studies suggested that CD28 and CD57 expression are mutually exclusive in human T cells,¹⁰^,²² i.e. under persistent antigenic stimulation early-differentiated memory CD28⁺ CD57⁻ T cells are gradually converted into late-differentiated CD28⁻ CD57⁺ T cells. However, this idea was disputed by Brenchley et al.⁷ who found that both CD28⁺ CD57⁺ and CD28⁻ CD57⁻ T cells were definitely detectable in the peripheral blood of HIV-positive patients and comprised up to 20% of the memory CD8⁺ T-cell pool. Moreover, it was clearly shown that CD8⁺ CD28⁺ CD57⁺ and CD8⁺ CD28⁻ CD57⁺ T cells have undergone the same number of cell divisions and have the shortest telomeres, whereas CD8⁺ CD57⁻ T cells have undergone fewer cell divisions than CD8⁺ CD57⁺ T cells irrespective of CD28 expression.⁷ Based on these results Brenchley et al.⁷ suggested that expression of CD57 alone most accurately predicts replicative senescence of CD8⁺ T cells. However, considering that the loss of CD28 on human T cells is a definite consequence of chronic antigenic stimulation (because CD8⁺ CD28⁻ T cells are virtually absent in the umbilical cord and neonatal blood and gradually expand throughout life¹⁵^,²³), it is rational to assume that CD8⁺ CD28⁻ CD57⁻ T cells are on their way to terminal differentiation and will gain CD57 after some additional rounds of antigenic stimulation. Indeed, Weekes et al.²⁴ showed that both CD28⁻ CD57⁻ and CD28⁻ CD57⁺ CD8⁺ T-cell subsets represent different activation states of the same lineage. However, it is not impossible that for still unelucidated reasons CD28⁻ CD57⁻ T cells will never gain CD57 expression, even after reaching the stage of late differentiation.

In this review the term ‘highly antigen experienced CD8⁺ T cells’ is used to describe both CD8⁺ CD57⁺ and CD8⁺ CD28⁻ T lymphocytes. One should remember that in various papers these T cells are defined as either CD8⁺ CD28⁻²^,³^,¹⁵^,²⁵^–²⁸ or CD8^+/highCD57⁺⁷^,¹⁴^,²⁹^–³⁴ or sometimes as CD8⁺ CD28⁻ CD57⁺,¹⁰^,²²^,²⁴^,³⁵ but actually all of the cases deal with the oligoclonally expanded CD8⁺ T cells, generated in response to chronic antigenic stimulation.

Features of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Generally CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are defined as antigen-specific, highly oligoclonally expanded, terminally differentiated, senescent, functionally competent memory/effector T lymphocytes that have undergone many rounds of cell divisions (it is exhibited by their shortened or eroded telomeres),³^,⁵^,¹⁵ show a dramatic decrease in or loss of telomerase activity⁵ and exhibit lower expression level of genes involved in cell-cycle regulation.¹¹ Often CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are characterized by their limited proliferative capacity or even their inability to proliferate under stimulation³^,⁷^,¹¹^,¹⁵^,²⁸ and are considered to have reached the state of replicative senescence or so-called ‘clonal exhaustion’.⁷^,¹¹ However, this approach seems to be incorrect, as discussed below.

Notably, these memory/effector CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells tend to express CD45RA rather that CD45RO,¹⁸^,³⁶ although for many years these CD45 isoforms were used to differentiate naive (CD45RA⁺/CD45RO⁻) and memory (CD45RA⁻/CD45RO⁺) T cells.¹⁸ Recently it was proposed that the CD45RA⁻/CD45RO⁺ phenotype may be a more reliable marker of T-cell activation, whereas CD45RA expression may better define the state of quiescence¹⁸^,³⁷ or ‘senescence’.³⁶

Proliferative capacity CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

The prevailing concept that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are unable to proliferate under antigen stimulation⁷^,¹⁵^,²⁸^,³⁴^,³⁸ was challenged by several groups who unequivocally demonstrated that these T cells are able to proliferate under certain stimulation conditions²⁵^,³⁹^–⁴² or may even show higher proliferation compared with their CD57⁻ counterparts.⁴⁰ Chong et al.⁴⁰ suggested that the inability of CD8⁺ CD57⁺ T cells to prolifetare under stimulation was associated with carboxyfluorescein succinimidyl ester (CFSE), a dye used to measure T-cell proliferation in previous experiments. They showed that cell death (defined by 7-amino-actinomycin D uptake) of CD8⁺ CD57,⁺ but not CD8⁺ CD57⁻ T cells was significantly higher in the presence of CFSE and presumed that the proliferative deficiency of CD8⁺ CD57⁺ T cells described in previous reports was associated with CFSE-caused cell death rather than with their natural inability to divide under stimulation.⁴⁰ Although it is known that generally CFSE is non-toxic to T cells, Chong et al. postulated that it may have toxic effect on CD8⁺ CD57⁺ T cells and should not be used to determine proliferation of this particular T-cell subset. Although underlying mechanisms of this distinctive toxicity remain to be elucidated, they hypothesized that it may be associated with the propensity of CFSE to non-specifically bind cytoplasmic proteins and interfere with intracellular pathways essential for the survival of CD8⁺ CD57⁺ T cells.⁴⁰ Another critical point is that Chong et al.⁴⁰ used human serum albumin rather than fetal calf serum in their proliferation assays because they found that proliferation of CD8⁺ CD57⁺ T cells was severely impaired in fetal calf serum.

How are ‘senescent’ CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells able to proliferate if they have critically shortened telomeres³^,⁵^,³⁸ and show loss of telomerase activity?³^,⁵^,³⁸ One possible explanation is that they need specific co-stimuli and certain cytokines, which are able to induce transient up-regulation of telomerase activity and enable these cells to divide. Indeed, Plunkett et al.³⁹ found that the use of irradiated peripheral blood mononuclear cells as a source of multiple co-stimulatory ligands provided by B cells, DCs and macrophages induced significant telomerase activity and proliferation in CD8⁺ CD28⁻ T cells compared with anti-CD3 stimulation alone. They also found that co-stimulatory molecules such as CD134 (OX40), CD137 (4-1BB) and CD278 (ICOS) were all rapidly up-regulated on CD8⁺ CD28⁻ T cells after stimulation with anti-CD3 antibodies, and that chimeric receptors containing the signalling domains of these molecules could induce telomerase activity in primary human CD8⁺ T cells.³⁹ Similar results were obtained by Kober et al.⁴², who found that appropriate co-stimuli (especially signalling through 4-1BB and OX40) induced proliferation of CD8⁺ CD28⁻ T cells. Several groups demonstrated that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are able to proliferate if co-stimulation is provided by certain cytokines, such as interleukin-2 (IL-2)⁴⁰ or IL-15.⁴¹

In summary, CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are able to proliferate, but they need specific milieu consisting of special distinctive co-stimulatory signals and/or particular cytokines.³⁹^–⁴² Obviously these peculiar circumstances were not properly taken into account in previous experiments, which revealed limited proliferative capacity of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells.

Dilemma of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell senescence

Considering unequivocal proliferative capacity of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells we meet with some conceptual problems, because these T cells are generally described as replicatively senescent and terminally differentiated.³^,⁵^,⁷^,³⁸ However, cellular (or replicative) senescence is clearly defined by several salient characteristics (precisely reviewed in refs ⁴³^,⁴⁴) with one of the main hallmarks of senescent cells being their permanent and most importantly irreversible cell cycle arrest, which cannot be overcome by any known physiological stimuli.⁴⁴^,⁴⁵ This infers that highly antigen experienced T cells defined by the loss of CD28 (or gain of CD57) are not truly senescent, because they are able to enter the active cell cycle and proliferate under certain stimulation conditions, as described above. At this point, it should be emphasized that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells can be divided into dictinct subsets, according to their ability to up-regulate telomerase activity, proliferative capacity and expression of CD27 molecules.³⁹^,⁴⁶^,⁴⁷ There is evidence, that the expression of CD27 may allow us to identify CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells that are closest to the terminal differentiation and senescence. It was clearly demonstrated that CD27-negative CD8⁺ CD28⁻ T cells have the shortest telomeres, show decreased telomerase activity and reduced capacity to proliferate after activation with anti-CD3 and irradiated pAPCs compared with CD27-positive T cells, indicating that CD27-negative CD8⁺ CD28⁻ T cells had differentiated to a point where co-stimulatory signals are no longer sufficient to induce telomerase activity.³⁹ Based on these results Plunkett et al.³⁹ suggested a linear differentiation pathway of CD8⁺ T cells from CD28⁺ CD27⁺ (early-differentiated) to CD28⁻ CD27⁺ (intermediate-differentiated) and finally to CD28⁻ CD27⁻ (late-differentiated) T cells upon repeated stimulation in vitro. The same dynamics of CD28 and CD27 expression during the differentiation process of CD8⁺ T cells was described in vivo by Appay et al.⁴⁶ and Papagno et al.⁴⁷ who found that during the early phase of acute HIV infection, there was an increase in HIV-specific CD8⁺ CD28⁺ CD27⁺ T cells,⁴⁶^,⁴⁷ which differentiated rapidly (within 2–4 weeks) into CD8⁺ CD28⁻ CD27⁺ T cells⁴⁶ and gradually gained CD57 expression.⁴⁷ Towards the end of acute HIV infection substantial, but low numbers of CD8⁺ CD28⁻ CD27⁻ T cells were detected.⁴⁶ Similar phenotypes (i.e. predominance of CD28⁻ CD27⁺ and low numbers of CD28⁻ CD27⁻ HIV-specific CD8⁺ T cells) were observed during chronic HIV infection,⁴⁶ implying that the majority of HIV-specific CD8⁺ CD28⁻ T cells do not reach the late-stage differentiation, defined by loss of CD27 expression.

Summarizing the data on CD28, CD57 and CD27 expression on CD8⁺ T cells, it appears that CD8⁺ CD28⁻ CD27⁻ (CD8⁺ CD57⁺ CD27⁻) T cells are possibly closest to terminal differentiation and replicative senescence,⁴⁸ but even these T cells are not truly senescent because they are still able to reconstitute telomerase activity and proliferate albeit to a significantly lesser extent than other CD8⁺ T-cell subsets.³⁹^,⁴⁸

Apoptotic potential of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Various authors provide conflicting data regarding CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell sensitivity to apoptosis. Some²^,⁷^,⁴⁹^,⁵⁰ claim that these T cells are very susceptible to activation-induced apoptosis because of increased expression of Fas, caspase-3 and decreased expression of anti-apoptotic molecules such as survivin and heat-shock protein 27 (hsp 27), while others¹⁶^,⁵¹^,⁵² indicate that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells display high resistance to apoptosis and thereby progressively accumulate throughout a lifetime.³⁸ Indeed, several studies demonstrated that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells show alterations in apoptosis because of up-regulation of the phosphoinositide 3-kinase pathway [which renders resistance to Fas (CD95) ligation-induced apoptosis]⁵³ and up-regulation of multifunctional anti-apoptotic factor hsp 27.³³ Another change in the survival pathways in CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells may be the result of up-regulation of various inhibitory natural killer cell receptors (iNKRs), such as CD94/NKG2A, the expression of which is associated with decreased susceptibility to apoptosis and elevated levels of anti-apoptotic molecule Bcl-2.⁵⁰ On the other hand it would be difficult to dispute CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell susceptibility to programmed cell death, because it was clearly demonstrated by several groups using reliable approaches to detect apoptosis, such as (i) annexin V binding assay,² (ii) propidium iodide uptake,⁷ (iii) binding (consumption) of substrate of activated caspase-3.⁷ How can we explain the results showing that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are highly resistant to apoptosis? At this point the data of Wood et al.⁵⁴ are of interest; they found that there was significantly more apoptosis of CD8⁺ CD57⁺ T lymphocytes compared with CD8⁺ CD57⁻ T lymphocytes in both normal and HIV-infected subjects. However, with advanced HIV infection, at a time when the total numbers of lung CD8⁺ CD57⁺ T cells were increasing, the percentage of CD57⁺ T cells undergoing apoptosis declined, especially in subjects with CD4⁺ T-cell counts under 200 cell/μl.⁵⁴ Wood et al.⁵⁴ suggested that particularly in late-stage HIV infection CD8⁺ CD57⁺ T cells fail to undergo normal apoptosis. It is plausible that this phenomenon (i.e. dysregulation of apoptosis in a subset of CD8⁺ CD57⁺ T cells) may be characteristic of various other advanced conditions associated with persistent antigenic stimulation. Again, it should be emphasized that besides irreversible block of proliferative ability (which is an unequivocal characteristic of cellular senescence), another important feature of some (but not all⁴³) senescent cells is their resistance to apoptosis.⁴³^,⁵²^,⁵⁵ As we discussed above, CD8⁺ CD28⁻ (CD8⁺ CD57⁺) cannot be defined as senescent (because they are able to proliferate under certain activation conditions), so it should not be surprising that these T cells are susceptible to apoptosis. However, it was also stated above that CD27-negative CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells have the shortest telomeres (compared with their CD28⁻ CD27⁺ and CD28⁺ CD27⁺ counterparts), show impaired ability to reconstitute telomerase activity and decreased proliferative capacity, so they may represent CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells that are approaching the state of true replicative senescence.⁴⁸ Hence the assumption that particularly these late-differentiated CD27-negative CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells begin to acquire other cellular senescence-associated features, such as resistance to apoptosis, cannot be refuted.

In summary, the most likely scenario considering apoptotic potential of highly antigen-experienced CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells would be that a proportion of these T cells (especially in an intermediate-differentiated, CD27-positive CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell compartment) are prone to apoptosis and die rapidly after antigen stimulation,²^,⁷ whereupon they are counterbalanced by newly generated CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells during chronic immune activation.² Another proportion of the intermediate-differentiated T cells are resistant to apoptosis and some of them may also further proliferate and differentiate into late-differentiated CD27-negative CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells, the great majority of which are highly resistant to apoptosis. CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells that acquire resistance to apoptosis accummulate throughout a lifetime leading to dramatic expansion of this T-cell population.⁵⁴ Most probably the resistance to apotosis is acquired in certain states with persistent antigenic stimulation⁵⁴ and is associated with more advanced differentiation. Therefore, it appears that not all highly antigen-experienced CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are destined to reach true senescence (as this would probably lead to disastrous accumulation of oligoclonal T cells) and a significant proportion of them die at an intermediate stage of differentiation. Only those CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells that become late-differentiated (CD27-negative) start to gain properties of true cellular senescence (i.e. they show altered proliferative capacity, acquisition of resistance to apoptosis) and eventually become truly senescent. A proposed model of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell apoptotic and proliferative potential is depicted in Fig. 1.

A model of CD8⁺ T-cell differentiation pathways during chronic immune activation. Under persistent antigen stimulation a proportion of early-differentiated CD8⁺ CD27⁺ CD45RA⁻ CD28⁺ CD57⁻ T cells may develop functional unresponsiveness and become exhausted (coloured in black), i.e. they up-regulate programmed death 1 (PD-1) expression, lose their proliferative capacity and functional activity. Another proportion of early-differentiated T cells further differentiate leading to the generation of oligoclonally expanded, intermediate-differentiated CD8⁺ CD27⁺ CD45RA^+/− CD28⁻/CD57⁺ memory/effector T-cell population with eroded telomeres. A proportion of these T cells (coloured in grey) are sensitive to apoptosis (because of over-expression of caspase-3 and down-regulation of survivin, hsp 27) and undergo programmed cell death under activation by cognate antigen. However, some intermediate-differentiated CD8⁺ CD27⁺ CD45RA^+/− CD28⁻/CD57⁺ T cells may acquire resistance to apoptosis [as the result of over-expression of phosphoinositde 3-kinase (PI3-K), Bcl-2, heat-shock protein 27 (hsp 27) which may be induced under certain conditions associated with chronic antigenic stimulation] and exert their effector function (cytotoxic or immunosuppressive, depending on a subset). Moreover, if antigen is presented by professional antigen-presenting cells, which are able to provide a selection of special co-stimulatory ligands (e.g. trigger signalling via OX-40, 4-1BB, ICOS) in a milieu of certain cytokines (e.g. interleukin-2, -15), the intermediate-differentiated CD8⁺ CD27⁺ CD45RA^+/− CD28⁻/CD57⁺ T cells can transiently up-regulate telomerase activity and proliferate, expanding the clone as well as further differentiate into late-differentiated CD8⁺ CD27⁻ CD45RA⁺ CD28⁻/CD57⁺ T cells, which have considerably reduced ability to up-regulate telomerase activity, decreased proliferative capacity, the majority of them are resistant to apoptosis and show robust effector activity. A minor proportion of these late-differentiated T cells may still be sensitivie to apoptosis (coloured in grey). It is likely that apoptosis-resistant late-differentiated T cells might be able to further differentiate and reach the terminal stage of replicative senescence, which is characterized by irreversible cell-cycle arrest, high resistance to apoptosis and vigorous effector activity.

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell subsets

Various authors describe CD8⁺ CD28⁻ T cells as either immunosuppressive⁵⁶^–⁶¹ or cytotoxic,²^,⁶²^–⁶⁵ whereas CD8⁺ CD57⁺ T cells in the majority of cases are described as highly cytotoxic.¹⁰^,³⁰^–³²^,⁶⁶^,⁶⁷ It was also shown that CD57 expression strongly correlates with simultaneous expression of granzymes and perforin in CD8⁺ T cells.⁶⁸ Therefore it could be presumed that CD8⁺ CD28⁻ T cells that are negative for CD57 tend to be immunosuppressive, whereas CD57-positive T cells show cytotoxic activity. In this view CD57 could be a marker enabling us to differentiate between suppressive and cytotoxic CD8⁺ CD28⁻ T cells. However, several studies described apparent immunosuppressive activity of CD8⁺ CD57⁺ T cells,⁶⁹^–⁷¹ challenging CD57 as a definite marker associated with cytotoxicity.

Cytotoxic CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell subsets

Numerous studies showed that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells express perforin, granzymes, granulysin and have high cytotoxic potential.³¹^,³²^,⁶³^–⁶⁷^,⁷²^,⁷³ Importantly, expression of these cytolytic molecules in CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells is substantially higher than in their CD28⁺ (CD57⁻) counterparts.³¹^,³²^,⁶⁴^–⁶⁷^,⁷² One of the genes most over-expressed in CD8⁺ CD57⁺ (versus CD8⁺ CD57⁻) T cells codes for granulysin which is a critical effector in the CTL response to intracellular pathogens and tumour cells, also acts as a chemoattractant and pro-inflammatory activator.³¹ Interestingly, some functional cytotoxic CD8⁺ CD57⁺ T cells under certain conditions may in parallel secrete a soluble glycoprotein capable of counteracting their cytolytic activity.³⁴

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells may produce high levels of immunomodulatory cytokine IFN-γ¹⁰^,³¹^,⁶²^,⁶⁴^,⁶⁶^,⁶⁷^,⁷⁴ and pro-inflammatory cytokine tumour necrosis factor-α (TNF-α).³¹^,³⁴^,⁴⁰^,⁷⁴ Production of these cytokines is more prominent in CD8⁺ CD28⁻ (CD8⁺ CD57⁺) than in CD8⁺ CD28⁺ (CD8⁺ CD57⁻) T cells.³¹^,³⁴^,⁶²^,⁶⁴^,⁶⁷^,⁷⁴ It was found that the increase of IFN-γ production through ageing correlates with the expanded CD8⁺ CD57⁺ T-cell population, implying that these T cells may be a source of elevated IFN-γ production.¹⁰ Another study suggested that elevated circulating IFN-γ-producing CD8⁺ CD28⁻ T cells might be involved in the pathogenesis of autoimmune response in Graves’ disease, because Graves’ ophthalmopathy was correlated with the prevalence of IFN-γ-producing CD8⁺ CD28⁻ (also CD4⁺ CD28⁻) T cells.⁶²

A less-described characteristic of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells is their ability to produce IL-5,²⁵^,⁴⁰ a cytokine that drives the differentiation of eosinophils in humans.⁴⁰ Hamzaoui et al.⁶⁵ showed that CD8⁺ CD57⁺ T cells were increased in induced sputum of patients with asthma and highly expressed perforin, especially in severe asthmatics and were implied to play a role in mediating asthma-associated inflammation. However, it cannot be excluded that secretion of IL-5 (which was not investigated by Hamzaoui et al.) could also contribute to this effect because it is well known that eosinophils play a critical role in asthma pathology.⁷⁵

Immunosuppressive CD8⁺ CD28⁻ and CD8⁺ CD57⁺ T-cell subsets

T-cell-mediated immunosuppression conception was initially proposed in early 1970s and was claimed to be mediated by CD8⁺ T cells, but later the interest of T-cell suppression models waned and the idea of suppressor T cells was abandoned.⁷⁶ After the revival of T-cell-mediated immunosuppression conception in mid 1990s for some time CD4⁺ regulatory T (Treg) cells were most extensively studied, until CD8⁺ T cells with apparent immunosuppressive properties were independently characterized by several groups.⁵⁶^,⁵⁸^,⁶⁹^,⁷⁶^–⁸⁴ There are several types of human CD8⁺ suppressor T (Ts) cells, such as (i) CD8⁺ CD28⁻ FOXP3⁺ Ts cells,⁵⁶ (ii) IL-10-secreting CD8⁺ CD28⁻ FOXP3⁻ Ts cells,⁵⁸ (iii) CD8⁺ CD57⁺ Ts cells,⁶⁹ as well as other subsets which do not fall into the scope of this review and are not discussed in more detail. They include (i) CD8⁺ CD25⁺ FOXP3⁺ Ts cells, which closely resemble CD4⁺ CD25⁺ FOXP3⁺ Treg cells,⁷⁹ (ii) CD8⁺ CCR7⁺ IL-10-producing Ts cells, mainly induced by plasmacytoid DCs,⁸¹^,⁸² (iii) HLA-E-restricted (Qa-1-restricted in mice) CD8⁺ Ts cells,⁷⁶^,⁷⁷ (iv) CD8⁺ CD103⁺ Ts cells.⁸³^,⁸⁴

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁺ T-cell subset

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁺ Ts cells are probably best characterized.⁵⁶^,⁸⁵^,⁸⁶ Nuclear transcription factor FOXP3 is considered to be one of the most relevant markers of many (but not all) immunosuppressive T cells, although it should be noted that unlike in mice, in humans FOXP3 is not an absolute marker of regulatory T lymphocytes, because its expression (together with CD25) is transiently induced in the great majority of activated naive ‘conventional’ CD4⁺ and CD8⁺ T cells.⁸⁷ However, the expression of FOXP3α, an isoform of FOXP3, prevails in the CD8⁺ CD28⁻ FOXP3⁺ Ts cell subset.⁵⁶

Gene profile analysis of CD8⁺ CD28⁻ FOXP3⁺ Ts cells showed a significant up-regulation of numerous genes with anti-apoptotic activity as well as genes that are involved in the WNT pathway, activation of which inhibits CD8⁺ T-cell proliferation and cytotoxic effector differentiation, namely IFN-γ and granzyme production.⁸⁶ Although CD8⁺ CD28⁻ FOXP3⁺ Ts cells induce genes that control cell growth machinery,⁸⁶ their cell-cycle arrest seems not to be irreversible because it was earlier shown that under certain stimulation conditions (e.g. high concentration of IL-2 in the presence of pAPC) these Ts cells are able to proliferate extensively.⁸⁸ CD8⁺ CD28⁻ FOXP3⁺ Ts cells with evident suppressive activity seem not to express CD57,⁸⁶ hence they may represent that minor subset of highly differentiated CD8⁺ T cells that are negative for both CD28 and CD57, as discussed earlier.

The mechanism of CD8⁺ CD28⁻ FOXP3⁺ Ts-mediated immunosuppression was unravelled by Suciu-Foca's group.⁵⁶^,⁸⁵ It differs from that mediated by other regulatory T lymphocytes because these Ts cells do not produce cytokines, have no killing capacity and their immunosuppressive activity is MHC-I class-restricted, i.e. antigen-specific.⁵⁶ It is presumed that strong up-regulation of transcription repressor Bcl-6 observed in CD8⁺ CD28⁻ FOXP3⁺ Ts cells accounts, at least in part, for their suppressive activity.⁸⁶

CD8⁺ CD28⁻ FOXP3⁺ Ts cells act on pAPCs (mainly DCs, also monocytes) as well as on non-pAPCs (endothelial cells) directly by cell-to-cell contact and render these APCs tolerogenic by inducing increased expression of immunoglobulin-like transcript 3 (ILT3) and ILT4, which belong to a family of immunoglobulin-like inhibitory receptors.⁸⁴^,⁸⁵ Ligand for ILT3 on T cells is unknown, whereas ILT4 binds to the non-polymorphic α3 domain of MHC-class Ia (HLA-A, HLA-B, HLA-C) and MHC-class Ib (HLA-G) molecules.⁸⁵ Over-expression of ILT3 and ILT4 on the surface of APCs markedly inhibits CD40-mediated activation of nuclear factor-κB, resulting in reduced capacity of APCs to transcribe nuclear factor-κB-dependent co-stimulatory molecules such as CD80 and CD86.⁸⁶^,⁸⁷ The generated tolerogenic ILT3^high ILT4^high APCs interact with naive CD4⁺ T cells which either become anergic and apoptose or gain constant CD25 and FOXP3 expression and acquire regulatory activity.⁸⁵ Similar to CD8⁺ CD28⁻ FOXP3⁺ Ts cells, these induced CD4⁺ Treg cells are antigen-specific and also act on APCs in a cytokine-independent, contact-dependent manner, inducing up-regulation of ILT3 and ILT4.⁵⁶^,⁸⁵ Furthermore, tolerogenic ILT3^high ILT4^high APCs can interact with naive CD8⁺ T cells, also inducing FOXP3 expression and converting their differentiation to CD8⁺ CD28⁻ FOXP3⁺ Ts cells.⁸⁵ Hence the interaction between MHC-class-I-specific CD8⁺ CD28⁻ FOXP3⁺ Ts or MHC-class-II-specific CD4⁺ CD25⁺ FOXP3⁺ iTreg cells and APCs is bidirectional, i.e. once the tolerogenic APCs are generated, they elicit further generation of iTreg and Ts cells.⁸⁵

In summary, according to the ‘tolerogenic cascade model’ proposed by Suciu-Foca's group,⁸⁵ CD8⁺ CD28⁻ FOXP3⁺ Ts cells set the cascade by generating the first wave of tolerogenic APCs. These tolerized APCs in turn anergize naive CD4⁺ and CD8⁺ T cells, which may acquire regulatory functions and in the same manner as the initial Ts cells further spread infectious tolerance. The emergence of Ts and iTreg cells ultimately down-regulates an efficient immune response mediated by the interaction of naive CD4⁺ and CD8⁺ T cells with ILT3^high ILT4^high tolerogenic APCs.⁸⁵ The delicate balance between immunity and tolerance may depend on the size of the effector populations or the prevalence of inflammatory or inhibitory cytokines that may affect the immunogenic or tolerogenic phenotype of APCs.⁸⁵

It should be emphasized that normal expression of ILT3 and ILT4 on pAPCs may be involved in suppressing an overactive immune response so warranting a balanced immune system function.⁸⁹ However, over-expression of these receptors seems to play a pivotal role in regulatory function of tolerogenic APCs, because no evidence was provided that any other inhibitory receptors are important for suppression of T-cell reactivity.⁸⁵^,⁸⁶

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁻ T-cell subset

Interleukin-10-secreting FOXP3-negative CD8⁺ CD28⁻ Ts cells are non-antigen-specific do not express CD56 and CD127 molecules; they are anergic and this state cannot be overcome by using various mitogens or mitogenic culture conditions.⁷⁸In vitro CD8⁺ CD28⁻ FOXP3⁻ Ts cells are generated from CD8⁺ CD28⁻ T cells under the action of IL-2 and IL-10 without the need for TCR stimulation.⁵⁸^,⁷⁸^,⁹⁰ Expression of glucocorticoid-induced TNF receptor-related protein has a role in generation but not suppressive function of CD8⁺ CD28⁻ FOXP3⁻ Ts cells.⁷⁸ They inhibit the APC activity of DCs, T-cell proliferation and cytotoxicity of CTL through the secretion of IL-10.⁵⁸^,⁷⁸^,⁹⁰ Corticosteroids influence neither generation nor suppressive function of CD8⁺ CD28⁻ FOXP3⁻ Ts cells.⁷⁸

Immunosuppressive CD8⁺ CD57⁺ T-cell subset

Several studies clearly demonstrated that CD8⁺ CD57⁺ T cells show immunosuppressive activity,⁶⁹^–⁷¹^,⁹¹ which is mediated by releasing a soluble, acid-, heat- and trypsin-resistant glycoprotein of 20 000–30 000 molecular weight, distinct from known cytokines.⁶⁹^,⁷¹ The soluble factor secreted by cultured CD8⁺ CD57⁺ T cells from bone-marrow-transplanted and HIV-infected patients has been shown to inhibit both the polyclonal activation and cytotoxic activity of T cells from healthy donors.⁶⁹^,⁷¹ Supernatants of CD8⁺ CD57⁺ T cells from patients with multiple myeloma suppressed pokeweed mitogen-driven or phytohaemagglutinin-driven T-cell proliferation as well as IgG and IgM production of pokeweed mitogen-stimulated peripheral blood lymphocytes of healthy individuals.⁶⁹ Suppression of immunoglobulin production was T-cell-dependent, suggesting that the soluble inhibitory factor acts on T-cell function.⁶⁹ Importantly, the CD8⁺ CD57⁺ T-cell-mediated inhibitory effect was significantly greater in patients with multiple myeloma than in healthy controls, although CD8⁺ CD57⁺ T cells from patients and controls were incubated at the same concentrations.⁶⁹ A similar effect was observed in HIV-infected and bone-marrow-transplanted patients, suggesting that the immunosuppressive CD8⁺ CD57⁺ T-cell population is expanded and more active in some pathological conditions.⁶⁹^,⁹²

Expression of natural killer cell receptors on CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Expression of NK cell receptors (NKRs) was initially identified on NK cells, later it was shown that functionally active NKRs are expressed on the surface of T-cell subsets and may regulate their functional activity.⁹³^–⁹⁵ The great majority of T cells expressing NKRs are included particularly within the CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population.¹⁶^,⁷²^,⁹⁶

The majority of human NKRs are specific for MHC-class I molecules⁹⁷ and are grouped into three families:⁷²^,⁹³^,⁹⁷ (i) killer immunoglobulin-like receptors, (ii) C-type lectin-like receptors (CD94/NKG2 heterodimers and NKG2D/NKG2D homodimer which is specific for MHC-class I chain-related molecules A and B), (iii) immunoglobulin-like transcripts (ILT, or leucocyte immunoglobulin-like receptors). The MHC-class I-restricted NKRs may be activating or inhibitory.⁷²^,⁹⁵^,⁹⁷ The activating NKRs (aNKRs) may act as co-stimulatory molecules that augment TCR-mediated activation⁷² or may mediate TCR-independent cytotoxicity of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells that express cytolytic molecules. Therefore aNKR-expressing T cells become like a component of innate immunity.⁵ The acquisition of inhibitory NKRs (iNKRs) on CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells has been associated with decreased susceptibility to apoptosis, elevated levels of anti-apoptotic molecule Bcl-2 and suppression of TCR-derived activation signals.⁵⁰^,⁷²^,⁹³ There are enough data to indicate that expression of iNKRs abolishes effector functions of CD8⁺ T cells.⁹³^,⁹⁵^,⁹⁸ Hence the expression of activating or inhibitory NKRs may contribute to the final outcome (stimulation versus inhibition) of T-cell activation,⁷²^,⁹³ but if both aNKRs and iNKRs are expressed on the same T cell, the effect of iNKRs tends to predominate.⁹⁹ The aNKRs may be expressed on both CD8⁺ CD28⁺ and CD8⁺ CD28⁻ T-cell populations, whereas the gain of iNKR expression on T cells is considered to reflect a history of chronic antigenic stimulation and these NKRs may limit the T-cell response to persistent antigen stimulation as well as prevent apoptosis.⁹⁵^,⁹⁷

Recently it was shown that surface expression of an inhibitory killer-cell lectin-like receptor G1 (KLRG1) identifies T cells that have undergone a large number of cell divisions.¹⁰⁰^,¹⁰¹ It was proposed that based on expression of CD28, CD57 and KLRG1, it is possible to distinguish T cells of distinct differentiation stages, namely naive T cells (CD28⁺/CD57⁻ KLRG1⁻), long-lived early memory T cells (CD28⁺/CD57⁻KLRG1⁺) and highly differentiated memory/effector T cells (CD28⁻/CD57⁺ KLRG1⁺).¹⁰¹ Although expression of KLRG1 on early memory (early-differentiated) CD8⁺ CD28⁺ CD27⁺ T cells increases with age, its expression is always higher on intermediate-differentiated CD8⁺ CD28⁻ CD27⁺ T cells and the greatest expression of KLRG1 is characteristic of late-stage differentiated CD8⁺ CD28⁻ CD27⁻ T cells both in young (< 35 years) and old (> 65 years) individuals.⁴⁸ In addition, KLRG1 expression positively correlates with the percentage of CD28⁻ CD27⁻ T cells present in the total CD8⁻ T-cell pool.⁴⁸ Also, there are convincing data that very high expression of KLRG1 on late-differentiated CD8⁺ CD28⁻ CD27⁻ T cells may, at least in part, account for their apparently decreased proliferative response to stimulation.⁴⁸

Expression of various non-MHC-class-I-specific NKRs on CD8⁺ CD28⁻ T cells was also described.⁷²^,⁹³ The majority of them are activating (CD16, CD161, CD244), whereas others serve as cell adhesion molecules (CD56).⁹³ Considering CD57, it also belongs to non-MHC-class-I-specific NKRs⁷²^,⁹³ and presumably functions as a cell adhesion molecule.¹¹^,⁹³^,⁹⁶

Late-differentiated CD28⁻ (CD57⁺) T cells versus PD-1-positive exhausted T cells

Late-differentiated CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells should not be confused with programmed death 1 (PD-1)-expressing T cells, which are also generated during chronic antigenic stimulation but, in contrast to the late-differentiated T cells, they are functionally unresponsive to further antigen stimulation, i.e. PD-1-positive T cells lose proliferative capacity (however this loss is not completely irreversible as in the case of cellular senescence) and effector functions and are defined as dysfunctional or exhausted.¹⁰²^–¹⁰⁴ Hence exhausted T lymphocytes represent a distinct state of T-cell differentiation which is characterized by defects in the ability to produce cytokines, poor cytotoxicity, loss of antigen-independent self-renewal and the ability to vigorously re-expand following antigen exposure.¹⁰² PD-1 (CD279) is a member of the CD28:B7 family of co-stimulatory/co-inhibitory receptors,¹⁰²^,¹⁰⁴ which is expressed on activated T cells, B cells, NK cells and monocytes.¹⁰⁴ Its expression does not increase with age on human T cells.⁴⁸ The majority of data describe negative regulation of T-cell activation, proliferation and effector functions by the ligands of PD-1 (PD-L1 and PD-L2)¹⁰⁵^,¹⁰⁶ whereas others claim that PD-1 ligands may enhance T-cell activation.¹⁰⁷

Naive CD8⁺ T cells exhibit no or little PD-1 expression but it is rapidlly up-regulated on activated T cells.¹⁰⁸ If the antigen is cleared, PD-1 expression decreases and functional memory CD8⁺ T cells are generated,¹⁰³ but it can be further up-regulated on these T cells when they are repeatedly activated.¹⁰⁸ However, in the presence of persistent antigen stimulation and constant activation of responder CD8⁺ T cells, PD-1 expression is not down-regulated on a proportion of activated CD8⁺ T cells and they become exhausted, i.e. functionally unresponsive to further antigen stimulation.¹⁰³^,¹⁰⁴ Notably, PD-1 is predominantly up-regulated on activated early/intermediate differentiated CD8⁺ T cells (CCR7⁻ CD27⁺), whereas its expression is depressed on CD8⁺ T cells that approach late-stage differentiation (CD8⁺ CCR7⁻ CD27⁻ CD45RA⁺ CD28⁻/CD57⁺),¹⁰⁸ indicating that regulation of this subset activity might occur at a different level independetly from PD-1.¹⁰⁸ It was suggested that immune exhaustion may play an important role in viral persistence during chronic infections,¹⁰⁴ because many pathogens that cause chronic infections exploit the PD-1/PD-L pathway to evade host immune effector mechanisms.¹⁰³ This assumption is supported by the fact that PD-1 expression is higher on HIV-, hepatitis B virus- or hepatitis C virus-specific T cells, while activated T cells specific for non-persisting viruses, such as vaccinia virus or influenza virus, have low PD-1 expression.¹⁰³ It was found that blockage of the PD-1 pathway in vitro and in vivo revives exhausted CD8⁺ T cells in chronically infected mice, primates and humans, identifying this pathway to be beneficial in clinical practice. However, Blackburn et al.¹⁰² showed that PD-1 expression is not uniform on subsets of exhausted CD8⁺ T cells because it varies dramatically in different tissues or anatomical sites, implying that various factors (e.g. PD-L1 expression, additional inhibitory receptors or inflammatory signals in tissue microenvironment) might be involved in influencing PD-1 expression and/or in preferential localization of exhausted CD8⁺ T cells.¹⁰² Hence the exhausted CD8⁺ T cells from various tissues would respond differently to therapeutic interventions based on PD-1 blockage.¹⁰² Furthermore Sauce et al.¹⁰⁸ showed that PD-1-expressing HIV-specific CD8⁺ T cells may display a clearly multifunctional profile (e.g. robust cytokine secretion and strong immediate functional capacity), implying that PD-1 expression does not always necessarily mean dysfunction or exhaustion. They postulated that under normal (i.e. not chronic) immune activation CD8⁺ T cells may naturally express PD-1 as a result of their differentiation and activation and use it as a self-regulating mechanism to prevent hyper-responsiveness (overgrowth and over-reactivity) without eventual transition to T-cell exhaustion.¹⁰⁸ However, under persistent antigenic stimulation (e.g. in the presence of high viral load during HIV infection) PD-1 is further permanently up-regulated, inducing CD8⁺ T-cell exhaustion.¹⁰⁸ In conlusion, it appears that during chronic immune activation, a proportion of T cells become functionally exhausted, while other T cells reach late-stage differentiation and sustain strong functional activity (Fig. 1). The mechanisms that direct T cells to exhaustion versus late-stage differentiation during persistent antigenic stimulation remain unknown.

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells in health and disease

Ageing

Natural ageing is associated with progressive oligoclonal accumulation of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population¹⁰^,¹⁰⁹^–¹¹¹ presumably as a result of lifetime exposure to common persistent antigens, e.g. pathogens, autoantigens and neoantigens.⁵^,¹¹ At birth essentialy all human T cells express CD28²³ and are CD57-negative;²¹ however, young adult individuals already have considerable accumulations of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T lymphocytes at frequencies of up to 20–30% of CD8⁺ CD28⁻⁵ and up to 20% of CD8⁺ CD57⁺ T cells,²⁴ whereas by age 80 years and above about 50–60% of CD8⁺ T cells lack CD28 expression.¹¹² Common persistent viral infections (especially human cytomegalovirus HCMV) are attributed to the expansion of the CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population with age.¹¹^,¹⁵^,¹⁰¹ As CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are highly oligoclonal, their accumulation leads to a reduction in the overall spectrum of antigenic specificities within the CD8⁺ T-cell compartment,³⁶ because the total number of peripheral T cells is tightly regulated by a negative-positive feedback loop, i.e. when peripheral T-cell numbers are high, negative feedback decreases the thymic output of naive T cells.¹⁰¹ In other words, oligoclonally expanded CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells fill the vital immunological space and render it inaccessible to the naive and early memory T-cell repertoire.¹¹^,¹⁵ Along with age-related thymic involution, this leads to significantly reduced antigenic diversity in elderly persons³⁸ and may be associated with detrimental immune incompetence in the elderly,¹⁵ i.e. reduced overall immune response to novel pathogens, tumour cells and vaccines.¹⁶^,¹¹³^–¹¹⁶ The age-related increase and predominance of the CD28⁻ (CD57⁺) T-cell population in the memory T-cell compartment is one of the parameters, defining the so-called immune risk phenotype, which predicts a higher premature all-cause 2-year mortality in octagenerians and nonagenerians.¹¹⁷ Other parameters of immune risk phenotype include CMV and Epstein–Barr virus (EBV) seropositivity, inverted CD4/CD8 ratio (< 1), low frequency of naive T cells (e.g. CD45RA⁺, CD28⁺, CD62L⁺, CD27⁺, CCR7⁺) and others.¹⁰¹^,¹¹⁷ Contraction of TCR diversity in old age may be accompanied by the induction of a diverse array of NKRs,¹⁶ as depicted above. Hence, the T-cell repertoire in the elderly consists of TCR-oligoclonal, but NKR-diverse, CD8⁺ CD57⁺ T cells.¹⁶ This secondary level of immune repertoire diversification may represent an age-related immunological adaptational changes.¹⁶

Importantly it was recently demonstrated that oligoclonal CD28⁻ T cells do not contain unique clones that are not present in the residual naive and early memory T-cell compartments.³⁶ Hence, the elimination of CD28⁻ T cells to create more immunological space and consequently allow the regeneration and rejuvenation of the aged T-cell system would not lead to loss of important specificities, because recruitment and propagation of relevant clones from naive and early memory compartments would be fully intact.³⁶

High-intensity physical activity

It is well described that acute bouts of aerobic exercise rapidly mobilize lymphocytes (especially CD8⁺ T cells) into the blood, resulting in a transient exercise-induced lymphocytosis, which is most likely governed by increased sympathetic nervous system activity and the resulting secretion of catecholamines.¹⁰¹^,¹¹⁸ During early stages of exercise recovery (usually within 30–60 min after exercise cessation) the blood lymphocyte count falls below resting values, as a result of selective extravasation of specific T-cell subsets from the blood to peripheral tissues resulting in transient exercise-induced lymphocytopenia.¹⁰¹ Most interestingly, it was shown that acute exercise elicits preferential mobilization of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells from peripheral tissues into the blood,¹⁰¹^,¹¹⁸ which is followed by preferential rapid removal of these T cells from the circulation to peripheral tissues during an early stage of exercise recovery.¹⁰¹^,¹¹⁸^,¹¹⁹ It is evident that highly antigen-experienced memory/effector CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are the most responsive to acute physical stress.¹⁰¹^,¹¹⁸

It was postulated that physical stress-induced transient rearrangement of effector T cells is an evolutionary response to fight-or-flight situations, when increased immune attendance may be required in the case of tissue injury and possible pathogen exposition.⁸⁵ However, Simpson in his excellent review¹⁰¹ contended that frequent T-cell shifts with acute exercise also could have accumulative long-term restorative effects on systemic immunity. The idea is based on the fact that during acute exercise blood lymphocytes are exposed to a milieu of pro-apoptotic signals that include increased levels of glucocorticoids, catecholamines, inflammatory cytokines and reactive oxygen species, which render them more susceptible to both intrinsic and extrinsic pathways of programmed cell death.¹⁰¹^,¹¹⁸ Lymphocytes do not appear to undergo apoptosis in the bloodstream, but after egress from blood during the recovery phase of exercise, a proportion of lymphocytes may undergo apoptosis in peripheral tissues.¹⁰¹^,¹¹⁸ Based on these arguments, Simpson hypothesized that exercise-induced preferential mobilization of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells into the blood and their subsequent partial deletion by apoptosis in the peripheral tissues, could capacitate naive T cells to occupy the vacated immunological space and thereby expand the naive T-cell repertoire, so shaping the ageing immune system and restoring the immunocompetence.¹⁰¹ This is an intriguing idea that would give additional scientific basis for the benefits of regular physical exercise on the immune system and overall human health. It is now known that blood lymphocytes mobilized by exercise are more susceptible to apoptosis and that CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells preferentially ingress and egress the blood in response to acute physical exercise.¹⁰¹^,¹¹⁸^,¹¹⁹ However, it is not known if certain T-cell populations (e.g. particularly late-differentiated T cells, as would be most desirable) have an increased susceptibility to exercise-induced DNA damage and apoptosis after exercise or whether healthy autologous lymphocytes are effected as well.¹⁰¹ Also it is not established whether the restoration of lymphocyte count to resting values 6–24 hr after exercise is mediated by resurgence of previously vacated CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells or by replacement of naive T cells (from thymus of extrathymic T-cell maturation sites) with different repertoire.¹⁰¹ Thus futher studies are needed in this promising field.

Cancer

Numerous studies have shown that the increase of the CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population is associated with malignancy. Increased numbers ot these T cells were found both in the tumour microenvironment and in the peripheral blood of patients with solid tumours²^,⁵⁸^,⁷²^,¹²⁰^–¹²⁴ and haemato-oncological diseases,²⁰^,⁵⁷^,⁶⁹^,¹¹⁶^,¹²⁵^,¹²⁶ including myelodysplasia.¹²⁷ A direct link between cancer and expansion of late-differentiated T cells was demonstrated in patients with head and neck cancer, as it was shown that the expanded CD8⁺ CD28⁻ T-cell population reached normal levels after the removal of the tumour.² The heterogeneity of the CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population is clearly demonstrated, when investigating its role in cancer pathology. In patients with melanoma the expanded CD8⁺ CD28⁻ T cells highly express perforin and may indicate an active immune response against the tumour.⁷² However, expanded CD8⁺ CD28⁻ T cells from lung cancer patients expressed significant levels of FOXP3 and were attributed to the immunosuppressive component of the antitumour immune response.¹²⁰ Filaci et al.⁵⁸ analysed biological samples from a series of 42 patients affected with various forms of cancer and found that tumour-infiltrating CD8⁺ CD28⁻ T cells showed secretion of both regulatory and effector cytokines, a likely consequence of the mixed composition of this T-cell population. In our laboratory we showed for the first time that melanoma patients with a lower level (< 23%) of CD8⁺ CD57⁺ T lymphocytes in the peripheral blood CD8⁺ T-cell population before treatment with adjuvant IFN-α2b survived longer than patients with a higher level (> 23%) of CD8⁺ CD57⁺ T cells.¹²¹ However, we observed the opposite trend in patients with advanced renal cell carcinoma because treatment with adjuvant IFN-α2b significantly increased the survival of patients with a higher level (> 30%) of CD8⁺ CD57⁺ T cells, whereas no increase in the survival was observed in patients with renal cell carcinoma with a lower level (< 30%) of CD8⁺ CD57⁺ T cells; moreover, a tendency towards decreased survival was observed in the latter group of renal cell carcinoma patients.¹²² We have also found that during treatment with IFN-α, lower pre-treatment values of CD8⁺ CD57⁺ T cells tend to increase (IFN-α promotes their expansion and survival), whereas higher pre-treatment values tend to decrease (there is evidence that IFN-α may eliminate over-activated T cells¹²⁸). Hence, IFN-α seems to induce the opposite changes in peripheral blood CD8⁺ CD57⁺ T-cell levels (i.e. increase versus decrease) depending on their pre-treatment values.¹²⁹ Collectively our data suggest that in melanoma patients the cytotoxic subsets of the CD8⁺ CD57⁺ T-cell population may predominate while in patients with renal cell carcinoma the expansion of its immunosuppressive subsets may prevail. It is likely that the composition (predominance of cytotoxic versus immunosuppressive) subsets of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population may differ in various types of cancer or even between individual patients with the same oncological disease (our unpublished data from an ongoing study).

Chronic viral infections

The increase of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population is observed in individuals with chronic viral infections such as HIV,⁷^,²⁸^,³¹ HCMV,³⁵^,¹³⁰^,¹³¹ EBV,¹⁵^,¹³² hepatitis C virus,¹³³ human parvovirus B₁₉,¹³⁴ and also in patients with Kaposi sarcoma,¹⁴ as well as in children after natural acute measles infection, but not after vaccination.¹³⁵ In otherwise healthy elderly individuals, CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells are frequently specific for HCMV and EBV antigens,¹¹^,¹⁵ indicating that various common chronic viral infections, not age per se, are the prime driving force of oligoclonal T-cell accumulation in the elderly.¹¹

Recent data showed that a higher frequency of CD8⁺ CD28⁻ CD57⁺ T cells among HIV-infected women was associated with subclinical carotid artery disease.¹³⁶ It was also shown that the increase of CD8⁺ CD28⁻ T cells in early-stage HIV infection is associated with more rapid progression to AIDS.¹³⁷

Interestingly, during chronic HIV infection the whole CD8⁺ T-cell population displays clear enrichment of late-differentiated CD8⁺ CD28⁻ CD27⁻ T cells showing a different phenotypic distribution from that of the HIV-specific CD8⁺ T cells, which predominantly demonstrate phenotype of intermediate differentiation (i.e CD28⁻ CD27⁺).⁴⁶ This suggests that HIV is not the sole cause of the differentiation phenotype changes undergone by the whole CD8⁺ T-cell population in HIV-infected patients. It is not surprising, because other opportunistic infections [in particular (HCMV) which, in contrast to chronic HIV infection, is associated with large oligoclonal expansion of late-differentiated CD8⁺ CD28⁻ CD27⁻ T cells] might be activated, especially in the context of HIV-induced immunosuppression.⁴⁶

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells may have a dual role in chronic viral infections. On the one hand their oligoclonal expansion and over-crowding of immunological space is related to increased occurence of opportunistic infections and cancers,¹¹^,³⁶ as was demonstrated even in young well-treated HIV-infected individuals.¹⁴ On the other hand the expanded CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population may be an important player in the antiviral immune response with cytotoxic activity and a protective role,³⁵^,⁷³ represented by high expression of perforin and secretion of cytokines, such as IFN-γ and/or TNF-α.³⁵^,⁷⁴ However, it should be noted that in HIV infection, IFN-γ and TNF-α produced by CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells may have an ambivalent action – they may not only enhance antiviral immunity, but promote apoptosis of CD4⁺ T cells as well. Moreover, TNF-α can up-regulate transcription of the HIV genome.⁷⁴

Of great interest are the results of Scheinberg et al.,¹³⁸ who performed a comprehensive analysis of CMV-specific T-cell immunity in HLA-matched donors and recipients before and after haematopoietic stem cell transplantation (HSCT) to define parameters, determining the successful transfer of antiviral T-cell immunity. One of the parameters studied was the phenotypic profile (surface expression of CD27, CD57), representing T-cell differentiation, namely early-differentiated memory T cells were defined as CD27⁺ CD57⁻ CD45RO⁺ and late-differentiated T cells were defined as CD27⁻ or CD57⁺. It was found that a higher frequency of CD8⁺ CD27⁺ and a lower frequency of CD8⁺ CD27⁻ HCMV-specific memory T cells were observed in donors of recipients who did not experience CMV reactivation compared with donors of recipients who experienced one or more reactivations. No such correlations were observed when analysing phenotypes of HCMV-specific CD4⁺ T cells. Furthermore, the frequency of early-differentiated CMV-specific CD8⁺ CD57⁻ memory T-cell-mediated responses in the donor appeared to confer protection from HCMV reactivations on the recipient. In conclusion, the study by Scheinberg et al. revealed that the fate of HCMV-specific T cells that are adoptively transferred during HSCT is likely to be determined by the characteristics of the response in the donor, i.e. specific T-cell responses that are less differentiated in the donor tend to persist in the corresponding recipient; conversely, those T-cell responses that are more differentiated in the donor show either decrease in frequency or are not identified at all in the recipient.¹³⁸ The data suggest that both proliferative capacity and survival of donor late-differentiated CD8⁺ CD57⁺ T cells are limited following their transfer to HSCT recipients and the evaluation of HCMV-specific T-cell differentiation phenotype in the donor may serve as one of the parameters enabling us to predict reactivation of HCMV in the recipient after HSCT.

Non-viral infections

Several studies have shown that the CD8⁺ CD57⁺ T-cell population is increased in the peripheral blood of patients with pulmonary tuberculosis.²⁹^,³²^,¹³⁹ Interestingly, Sada-Ovalle et al.³² found that CD8⁺ CD57⁺ T cells from patients with pulmonary tuberculosis showed high cytotoxic activity although their cytotoxic capacity was lower than that of CD8⁺ CD57⁻ T cells, despite the fact that expression of perforin, granzyme A, IFN-γ and TNF-α was significantly greater in CD8⁺ CD57⁺ T cells.

It was also reported that CD8⁺ CD57⁺ Tcells were expanded in an immunocompetent patient with acute toxoplasmosis.³⁰ As these T cells produce large amounts of IFN-γ and IL-5 (which are crucial in the immune response against Toxoplasma gondii), it is possible that cytotoxic CD8⁺ CD57⁺ cells can prevent the reactivation of T. gondii in a similar manner because they control HCMV reactivation throughout a lifetime.³⁰

There are data that long-term decrease of CD57 expression is associated with chronic Lyme disease; however, one should take into account that in this case we are dealing with a subset of CD3-negative CD57-positive NK cells, not with T cells.¹⁴⁰

Autoimmune diseases

Quantitative changes of the CD8⁺ CD57⁺ T-cell population are observed in autoimmune diseases, such as multiple sclerosis,⁶¹ type 1 diabetes mellitus,⁶¹ Graves’ disease,⁶² ankylosing spondylitis,⁶⁴ pars planitis⁶⁷ and rheumatoid arthritis.¹⁴¹ The majority of autoimmune diseases (Graves’ disease,⁶² ankylosing spondylitis,⁶⁴ pars planitis,⁶⁷ dermatomyositis, polymyositis¹⁴²) are associated with the increase of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells, which show highly cytotoxic activity and may play an active role in the autoimmune response, and so are associated with more severe disease manifestation.⁶²^,⁶⁴^,⁶⁷ The decrease of CD8⁺ CD28⁻ T cells correlates with the clinical response to abatacept in patients with rheumatoid arthritis.¹⁴³ On the other hand Mikulkova et al.⁶¹ found that type 1 diabetes mellitus and multiple sclerosis were associated with a decrease of the CD8⁺ CD28⁻ T-cell population and they regarded these T cells as immunosuppressive although the expression of markers (e.g. FOXP3, IL-10, transforming growth factor-β), representing the immunosuppressive potential of T cells was not evaluated in their study.⁶¹ However, Tulunay et al.⁶⁰ found that systemic lupus erythematosus was associated with a significant decrease of CD8⁺ CD28⁻ T cells with apparent suppressive activity. Hence, it is rational to imply that some autoimmune diseases may be actually associated with the decrease of immunosuppressive subsets of a functionally heterogeneous CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell population.

Transplantation

Allogeneic solid organ or bone marrow transplantation is associated with oligoclonal expansion of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells,¹¹^,⁵⁹^,⁷⁰^,¹⁴⁴^,¹⁴⁵ which seem to exert immunosuppressive activity⁵⁹^,⁷⁰^,¹⁴⁴^–¹⁴⁶ and act as the primary effectors of tolerance in organ transplantation.¹⁴⁵ Emerging data suggest that the appearance of these T cells in transplant recipients is associated with better graft acceptance and stable function⁵⁶^,⁵⁹^,¹⁴⁴ as well as with reduced need for maintenance of iatrogenic immunosuppression.⁵⁹ CD8⁺ CD28⁻ FOXP3⁺ Ts cells were found in the circulation of patients within the first 6 months post-transplantation and persisted in recipients with no evidence of chronic rejection 3 years following transplantation.¹⁴⁶ It was also shown that in transplant recipients CD8⁺ CD28⁻ Ts cells could be detected as early as 1 month post-transplantation, whereas CD4⁺ CD25⁺ Treg cells became detectable at substantially later times (12 months or more).⁵⁶ It may be helpful to monitor levels of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells with immunosuppressive (as well as cytotoxic, which would be undesirable) phenotype in order to evaluate the immune status of allograft recipients and to modify regimens of immunosuppressive therapies.⁵⁹

Chronic alcoholism

Most chronic alcoholics (with or without liver disease) have stable expansion of CD8⁺ CD57⁺ cells.³^,¹⁴⁷ Most likely it is caused by hepatocyte injury-associated chronic antigenic exposure resulting from acetaldehyde–protein adducts or cryptic self-antigens released during episodes of liver parenchymal cell necrosis.³^,¹⁴⁷ Expansion of the CD8⁺ CD57⁺ T-cell subset may also be associated with chronic infections, which are characteristic of heavy drinkers.¹³^,¹⁴⁷

Chronic pulmonary diseases

Hamzaoui et al.⁶⁵ found that the CD8⁺ CD57⁺ T-cell population was significantly increased in induced sputum of patients with asthma, especially in those with severe disease. These cells highly expressed perforin and showed efficient cytotoxic activity, but the expression of IFN-γ in CD8⁺ CD57⁺ T cells was significantly lower in severe asthmatics compared with mild asthmatics and healthy controls.⁶⁵ Olloquequi et al.¹⁴⁸ reported significant and specific increase of CD3⁺ CD57⁺ T-cell density in ectopic pulmonary lymphoid follicles of patients with chronic obstructive pulmonary disease compared with non-smokers and smokers without chronic obstructive pulmonary disease. However, they performed immunohistochemical analysis of lymphoid follicles and did not differentiate the expression of CD57 between CD4⁺ and CD8⁺ T cells.¹⁴⁸ Yet there are data that both CD8⁺ CD28⁻ and CD4⁺ CD28⁻ T-cell populations are increased in patients with chronic obstructive pulmonary disease and their expansion is associated with chronic antigenic stimulation caused by noxious inhalants, which induce injury of epithelial and endothelial cells and elicit a dysregulated immune response.¹⁴⁹

Glossary

Abbreviations

Bcl-6: B-cell lymphoma 6 protein
CFSE: carboxyfluorescein succinimidyl ester
CTL: cytotoxic T lymphocyte
DC: dendritic cell
EBV: Epstein–Barr virus
FOXP3: forkhead helix box P3
HCMV: human cytomegalovirus
HNK-1: human natural killer cell carbohydrate antigen-1
HSCT: haematopoietic stem cell transplantation
hsp 27: heat-shock protein (molecular mass 27 000)
ICOS: inducible co-stimulator
IFN-α(-γ): interferon-α(-γ)
IL: interleukin
ILT: immunoglobulin-like transcript
KLRG-1: killer-cell lectin-like receptor G1
NKR: natural killer cell receptor (aNKR – activating, iNKR – inhibitory)
pAPC: professional antigen-presenting cell
PD-1: programmed death 1
PD-L (-1 or -2): programmed death ligand (-1 or -2)
TCR: T-cell receptor
Treg: T regulatory
Ts: T suppressor
TNF-α: tumour necrosis factor-α

References

1.Nagata T, Koide Y. Induction of specific CD8 T cells against intracellular bacteria by CD8 T-cell-oriented immunization approaches. J Biomed Biotechnol. 2010;2010:764542. doi: 10.1155/2010/764542. DOI: 10.1155/2010/764542. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Tsukishiro T, Donnenberg AD, Whiteside TL. Rapid turnover of the CD8+ CD28− T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol Immunother. 2003;52:599–607. doi: 10.1007/s00262-003-0395-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Arosa FA. CD8+ CD28− T cells: certainties and uncertainties of a prevalent human T-cell subset. Immunol Cell Biol. 2002;80:1–13. doi: 10.1046/j.1440-1711.2002.01057.x. [DOI] [PubMed] [Google Scholar]
4.Bernard A, Lamy L, Alberti I. The two-signal model of T-cell activation after 30 years. Transplantation. 2002;73:S31–5. doi: 10.1097/00007890-200201151-00011. [DOI] [PubMed] [Google Scholar]
5.Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158–69. doi: 10.1111/j.0105-2896.2005.00256.x. [DOI] [PubMed] [Google Scholar]
6.Boesteanu AC, Katsikis PD. Memory T cells need CD28 costimulation to remember. Semin Immunol. 2009;21:69–77. doi: 10.1016/j.smim.2009.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Brenchley JM, Karandikar NJ, Betts MR, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101:2711–20. doi: 10.1182/blood-2002-07-2103. [DOI] [PubMed] [Google Scholar]
8.Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol. 2002;2:251–62. doi: 10.1038/nri778. [DOI] [PubMed] [Google Scholar]
9.Merino J, Martínez-González MA, Rubio M, Inogés S, Sánchez-Ibarrola A, Subirá ML. Progressive decrease of CD8high+ CD28+ CD57− cells with ageing. Clin Exp Immunol. 1998;112:48–51. doi: 10.1046/j.1365-2249.1998.00551.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Bandrés E, Merino J, Vázquez B, Inogés S, Moreno C, Subirá ML, Sánchez-Ibarrola A. The increase of IFN-gamma production through aging correlates with the expanded CD8+high CD28− CD57+ subpopulation. Clin Immunol. 2000;96:230–5. doi: 10.1006/clim.2000.4894. [DOI] [PubMed] [Google Scholar]
11.Focosi D, Bestagno M, Burrone O, Petrini M. CD57+ T lymphocytes and functional immune deficiency. J Leukoc Biol. 2010;87:107–16. doi: 10.1189/jlb.0809566. [DOI] [PubMed] [Google Scholar]
12.Uusitalo M, Kivelä T. The HNK-1 carbohydrate epitope in the eye: basic science and functional implications. Prog Retin Eye Res. 2001;20:1–28. doi: 10.1016/s1350-9462(00)00018-5. [DOI] [PubMed] [Google Scholar]
13.Valenzuela HF, Effros RB. Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol. 2002;105:117–25. doi: 10.1006/clim.2002.5271. [DOI] [PubMed] [Google Scholar]
14.Unemori P, Hunt P, Leslie K, Sinclair E, Deeks S, Martin J, Maurer T. CD57+, a global marker of immunosenescence, is elevated in an atypical cohort of patients with Kaposi sarcoma and well-controlled HIV. Infect Agent Cancer. 2009;4:P43. [Google Scholar]
15.Weng NP, Akbar AN, Goronzy J. CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30:306–12. doi: 10.1016/j.it.2009.03.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Abedin S, Michel JJ, Lemster B, Vallejo AN. Diversity of NKR expression in aging T cells and in T cells of the aged: the new frontier into the exploration of protective immunity in the elderly. Exp Gerontol. 2005;40:537–48. doi: 10.1016/j.exger.2005.04.012. [DOI] [PubMed] [Google Scholar]
17.Nadareishvili ZG, Li H, Wright V, et al. Elevated pro-inflammatory CD4+ CD28− lymphocytes and stroke recurrence and death. Neurology. 2004;63:1446–51. doi: 10.1212/01.wnl.0000142260.61443.7c. [DOI] [PubMed] [Google Scholar]
18.Appay V, Rowland-Jones SL. Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol. 2004;16:205–12. doi: 10.1016/j.smim.2004.02.007. [DOI] [PubMed] [Google Scholar]
19.Ben-David H, Sharabi A, Dayan M, Sela M, Mozes E. The role of CD8+ CD28− regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand. Proc Natl Acad Sci USA. 2007;104:17459–64. doi: 10.1073/pnas.0708577104. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Ménager-Marcq I, Pomié C, Romagnoli P, van Meerwijk JP. CD8+ CD28− regulatory T lymphocytes prevent experimental inflammatory bowel disease in mice. Gastroenterology. 2006;131:1775–85. doi: 10.1053/j.gastro.2006.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Ortiz-Suárez A, Miller RA. A subset of CD8 memory T cells from old mice have high levels of CD28 and produce IFN-gamma. Clin Immunol. 2002;104:282–92. doi: 10.1006/clim.2002.5221. [DOI] [PubMed] [Google Scholar]
22.Sze DM, Giesajtis G, Brown RD, et al. Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8+ CD57+ CD28− compartment. Blood. 2001;98:2817–27. doi: 10.1182/blood.v98.9.2817. [DOI] [PubMed] [Google Scholar]
23.Jennings C, Rich K, Siegel JN, Landay A. A phenotypic study of CD8+ lymphocyte subsets in infants using three-color flow cytometry. Clin Immunol Immunopathol. 1994;71:8–13. doi: 10.1006/clin.1994.1044. [DOI] [PubMed] [Google Scholar]
24.Weekes MP, Wills MR, Mynard K, Hicks R, Sissons JG, Carmichael AJ. Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28− CD8+ T-cell population. Immunology. 1999;98:443–9. doi: 10.1046/j.1365-2567.1999.00901.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Fiorentini S, Malacarne F, Ricotta D, et al. Generation of CD28− cells from long-term-stimulated CD8+ CD28+ T cells: a possible mechanism accounting for the increased number of CD8+ CD28− T cells in HIV-1-infected patients. J Leukoc Biol. 1999;65:641–8. doi: 10.1002/jlb.65.5.641. [DOI] [PubMed] [Google Scholar]
26.Labalette M, Leteurtre E, Thumerelle C, Grutzmacher C, Tourvieille B, Dessaint JP. Peripheral human CD8+ CD28+ T lymphocytes give rise to CD28− progeny, but IL-4 prevents loss of CD28 expression. Int Immunol. 1999;11:1327–36. doi: 10.1093/intimm/11.8.1327. [DOI] [PubMed] [Google Scholar]
27.Lazuardi L, Herndler-Brandstetter D, Brunner S, Laschober GT, Lepperdinger G, Grubeck-Loebenstein B. Microarray analysis reveals similarity between CD8+ CD28− T cells from young and elderly persons, but not of CD8+ CD28+ T cells. Biogerontology. 2009;10:191–202. doi: 10.1007/s10522-008-9167-1. [DOI] [PubMed] [Google Scholar]
28.Vivar N, Thang PH, Atlas A, Chiodi F, Rethi B. Potential role of CD8+ CD28− T lymphocytes in immune activation during HIV-1 infection. AIDS. 2008;22:1083–6. doi: 10.1097/QAD.0b013e3282fce613. [DOI] [PubMed] [Google Scholar]
29.Fateminasab FD, Shahgasempour S, Mirsaeidi SM, Tabarsi P, Mansoori SD, Entezami Z. Increased activation and expansion of a CD57+ subset within peripheral CD8+ T lymphocytes in Mycobacterium tuberculosis-infected patients. Arch Iran Med. 2006;9:53–7. [PubMed] [Google Scholar]
30.García-Muñoz R, Rodríguez-Otero P, Galar A, Merino J, Beunza JJ, Páramo JA, Lecumberri R. Expansion of CD8+ CD57+ T cells in an immunocompetent patient with acute toxoplasmosis. Adv Hematol. 2009;209:173439. doi: 10.1155/2009/173439. DOI: 10.1155/2009/173439. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Le Priol Y, Puthier D, Lécureuil C, Combadière C, Debré P, Nguyen C, Combadière B. High cytotoxic and specific migratory potencies of senescent CD8+ CD57+ cells in HIV-infected and uninfected individuals. J Immunol. 2006;177:5145–54. doi: 10.4049/jimmunol.177.8.5145. [DOI] [PubMed] [Google Scholar]
32.Sada-Ovalle I, Torre-Bouscoulet L, Valdez-Vázquez R, Martínez-Cairo S, Zenteno E, Lascurain R. Characterization of a cytotoxic CD57+ T cell subset from patients with pulmonary tuberculosis. Clin Immunol. 2006;121:314–23. doi: 10.1016/j.clim.2006.08.011. [DOI] [PubMed] [Google Scholar]
33.Wood KL, Voss OH, Huang Q, Parihar A, Mehta N, Batra S, Doseff AI. The small heat shock protein 27 is a key regulator of CD8+ CD57+ lymphocyte survival. J Immunol. 2010;184:5582–8. doi: 10.4049/jimmunol.0902953. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Mollet L, Sadat-Sowti B, Duntze J, et al. CD8hi+ CD57+ T lymphocytes are enriched in antigen-specific T cells capable of down-modulating cytotoxic activity. Int Immunol. 1998;10:311–23. doi: 10.1093/intimm/10.3.311. [DOI] [PubMed] [Google Scholar]
35.Mendes AV, Kallas EG, Benard G, et al. Impact of cytomegalovirus and grafts versus host disease on the dynamics of CD57+ CD28− CD8+ T cells after bone marrow transplant. Clinics (Sao Paulo) 2008;63:667–76. doi: 10.1590/S1807-59322008000500016. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Weinberger B, Welzl K, Herndler-Brandstetter D, Parson W, Grubeck-Loebenstein B. CD28− CD8+ T cells do not contain unique clonotypes and are therefore dispensable. Immunol Lett. 2009;127:27–32. doi: 10.1016/j.imlet.2009.08.008. [DOI] [PubMed] [Google Scholar]
37.Dunne PJ, Faint JM, Gudgeon NH, et al. Epstein–Barr virus-specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood. 2002;100:933–40. doi: 10.1182/blood-2002-01-0160. [DOI] [PubMed] [Google Scholar]
38.Effros RB. Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. Exp Gerontol. 2011;46:135–40. doi: 10.1016/j.exger.2010.08.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Plunkett FJ, Franzese O, Finney HM, et al. The loss of telomerase activity in highly differentiated CD8+ CD28− CD27− T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007;178:7710–9. doi: 10.4049/jimmunol.178.12.7710. [DOI] [PubMed] [Google Scholar]
40.Chong LK, Aicheler RJ, Llewellyn-Lacey S, Tomasec P, Brennan P, Wang EC. Proliferation and interleukin 5 production by CD8hi CD57+ T cells. Eur J Immunol. 2008;38:995–1000. doi: 10.1002/eji.200737687. [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Chiu WK, Fann M, Weng NP. Generation and growth of CD28null CD8+ memory T cells mediated by IL-15 and its induced cytokines. J Immunol. 2006;177:7802–10. doi: 10.4049/jimmunol.177.11.7802. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Kober J, Leitner J, Klauser C, et al. The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells. Eur J Immunol. 2008;38:2678–88. doi: 10.1002/eji.200838250. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40. doi: 10.1038/nrm2233. [DOI] [PubMed] [Google Scholar]
44.Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192:547–56. doi: 10.1083/jcb.201009094. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.von Zglinicki T, Saretzki G, Ladhoff J, d'Adda di Fagagna F, Jackson SP. Human cell senescence as a DNA damage response. Mech Ageing Dev. 2005;126:111–7. doi: 10.1016/j.mad.2004.09.034. [DOI] [PubMed] [Google Scholar]
46.Appay V, Papagno L, Spina CA, et al. Dynamics of T cell responses in HIV infection. J Immunol. 2002;168:3660–6. doi: 10.4049/jimmunol.168.7.3660. [DOI] [PubMed] [Google Scholar]
47.Papagno L, Spina CA, Marchant A, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol. 2004;2:0173–85. doi: 10.1371/journal.pbio.0020020. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Henson SM, Franzese O, Macaulay R, et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood. 2009;113:6619–28. doi: 10.1182/blood-2009-01-199588. [DOI] [PubMed] [Google Scholar]
49.Borthwick NJ, Lowdell M, Salmon M, Akbar AN. Loss of CD28 expression on CD8+ T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol. 2000;12:1005–13. doi: 10.1093/intimm/12.7.1005. [DOI] [PubMed] [Google Scholar]
50.Wood KL, Twigg HL, 3rd, Doseff AI. Dysregulation of CD8+ lymphocyte apoptosis, chronic disease, and immune regulation. Front Biosci. 2009;14:3771–81. doi: 10.2741/3487. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Effros RB. Replicative senescence of CD8 T cells: potential effects on cancer immune surveillance and immunotherapy. Cancer Immunol Immunother. 2004;53:925–33. doi: 10.1007/s00262-004-0508-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Spaulding C, Guo W, Effros RB. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol. 1999;34:633–44. doi: 10.1016/s0531-5565(99)00033-9. [DOI] [PubMed] [Google Scholar]
53.Strauss G, Knape I, Melzner I, Debatin KM. Constitutive caspase activation and impaired death-inducing signaling complex formation in CD95-resistant, long-term activated, antigen-specific T cells. J Immunol. 2003;171:1172–82. doi: 10.4049/jimmunol.171.3.1172. [DOI] [PubMed] [Google Scholar]
54.Wood KL, Knox KS, Wang Y, Day RB, Schnizlein-Bick C, Twigg HL., 3rd Apoptosis of CD57+ and CD57− lymphocytes in the lung and blood of HIV-infected subjects. Clin Immunol. 2005;117:294–301. doi: 10.1016/j.clim.2005.09.009. [DOI] [PubMed] [Google Scholar]
55.Salminen A, Ojala J, Kaarniranta K. Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cell Mol Life Sci. 2011;68:1021–31. doi: 10.1007/s00018-010-0597-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Suciu-Foca N, Manavalan JS, Scotto L, et al. Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. Int Immunopharmacol. 2005;5:7–11. doi: 10.1016/j.intimp.2004.09.003. [DOI] [PubMed] [Google Scholar]
57.Urbaniak-Kujda D, Kapelko-Słowik K, Wołowiec D, et al. Increased percentage of CD8+ CD28− suppressor lymphocytes in peripheral blood and skin infiltrates correlates with advanced disease in patients with cutaneous T-cell lymphomas. Postepy Hig Med Dosw (Online) 2009;63:355–9. [PubMed] [Google Scholar]
58.Filaci G, Fenoglio D, Fravega M, et al. CD8+ CD28− T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol. 2007;179:4323–34. doi: 10.4049/jimmunol.179.7.4323. [DOI] [PubMed] [Google Scholar]
59.Lin YX, Wang LL, Yan LN, Cai P, Li B, Wen TF, Zeng Y. Analysis of CD8+ CD28− T-suppressor cells in living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2009;8:241–6. [PubMed] [Google Scholar]
60.Tulunay A, Yavuz S, Direskeneli H, Eksioglu-Demiralp E. CD8+ CD28−, suppressive T cells in systemic lupus erythematosus. Lupus. 2008;17:630–7. doi: 10.1177/0961203308089400. [DOI] [PubMed] [Google Scholar]
61.Mikulkova Z, Praksova P, Stourac P, et al. Numerical defects in CD8+ CD28− T-suppressor lymphocyte population in patients with type 1 diabetes mellitus and multiple sclerosis. Cell Immunol. 2010;262:75–9. doi: 10.1016/j.cellimm.2010.02.002. [DOI] [PubMed] [Google Scholar]
62.Sun Z, Zhong W, Lu X, Shi B, Zhu Y, Chen L, Zhang G, Zhang X. Association of Graves’ disease and prevalence of circulating IFN-gamma-producing CD28− T cells. J Clin Immunol. 2008;28:464–72. doi: 10.1007/s10875-008-9213-4. [DOI] [PubMed] [Google Scholar]
63.Fiorentino S, Dalod M, Olive D, Guillet JG, Gomard E. Predominant involvement of CD8+ CD28− lymphocytes in human immunodeficiency virus-specific cytotoxic activity. J Virol. 1996;70:2022–6. doi: 10.1128/jvi.70.3.2022-2026.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
64.Schirmer M, Goldberger C, Würzner R, Duftner C, Pfeiffer KP, Clausen J, Neumayr G, Falkenbach A. Circulating cytotoxic CD8+ CD28− T cells in ankylosing spondylitis. Arthritis Res. 2002;4:71–6. doi: 10.1186/ar386. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Hamzaoui A, Chaouch N, Grairi H, Ammar J, Hamzaoui K. Inflammatory process of CD8+ CD28− T cells in induced sputum from asthmatic patients. Mediators Inflamm. 2005;2005:160–6. doi: 10.1155/MI.2005.160. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.Ohkawa T, Seki S, Dobashi H, Koike Y, Habu Y, Ami K, Hiraide H, Sekine I. Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology. 2001;103:281–90. doi: 10.1046/j.1365-2567.2001.01248.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Pedroza-Seres M, Linares M, Voorduin S, Enrique RR, Lascurain R, Garfias Y, Jimenez-Martinez MC. Pars planitis is associated with an increased frequency of effector-memory CD57+ T cells. Br J Ophthalmol. 2007;91:1393–8. doi: 10.1136/bjo.2007.116277. [DOI] [PMC free article] [PubMed] [Google Scholar]
68.Chattopadhyay PK, Betts MR, Price DA, Gostick E, Horton H, Roederer M, De Rosa SC. The cytolytic enzymes granzyme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression. J Leukoc Biol. 2009;85:88–97. doi: 10.1189/jlb.0208107. [DOI] [PMC free article] [PubMed] [Google Scholar]
69.Frassanito MA, Silvestris F, Cafforio P, Dammacco F. CD8+/CD57+ cells and apoptosis suppress T-cell functions in multiple myeloma. Br J Haematol. 1998;100:469–77. doi: 10.1046/j.1365-2141.1998.00589.x. [DOI] [PubMed] [Google Scholar]
70.Gorochov G, Debré P, Leblond V, Sadat-Sowti B, Sigaux F, Autran B. Oligoclonal expansion of CD8+ CD57+ T cells with restricted T-cell receptor beta chain variability after bone marrow transplantation. Blood. 1994;83:587–95. [PubMed] [Google Scholar]
71.Sadat-Sowti B, Debré P, Mollet L, Quint L, Hadida F, Leblond V, Bismuth G, Autran B. An inhibitor of cytotoxic functions produced by CD8+ CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients. Eur J Immunol. 1994;24:2882–8. doi: 10.1002/eji.1830241145. [DOI] [PubMed] [Google Scholar]
72.Casado JG, Soto R, DelaRosa O, et al. CD8 T cells expressing NK associated receptors are increased in melanoma patients and display an effector phenotype. Cancer Immunol Immunother. 2005;54:1162–71. doi: 10.1007/s00262-005-0682-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Dolstra H, Preijers F, Van de Wiel-van Kemenade E, Schattenberg A, Galama J, de Witte T. Expansion of CD8+ CD57+ T cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection. Br J Haematol. 1995;90:300–7. doi: 10.1111/j.1365-2141.1995.tb05150.x. [DOI] [PubMed] [Google Scholar]
74.Eylar EH, Lefranc CE, Yamamura Y, Báez I, Colón-Martinez SL, Rodriguez N, Breithaupt TB. HIV infection and aging: enhanced Interferon- and Tumor Necrosis Factor-alpha production by the CD8+ CD28− T subset. BMC Immunol. 2001;2:10. doi: 10.1186/1471-2172-2-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
75.Wenzel SE. Eosinophils in asthma – closing the loop or opening the door? N Engl J Med. 2009;360:1026–8. doi: 10.1056/NEJMe0900334. [DOI] [PubMed] [Google Scholar]
76.Chess L, Jiang H. Resurrecting CD8+ suppressor T cells. Nat Immunol. 2004;5:469–71. doi: 10.1038/ni0504-469. [DOI] [PubMed] [Google Scholar]
77.Jiang H, Chess L. Qa-1/HLA-E-restricted regulatory CD8+ T cells and self-nonself discrimination: an essay on peripheral T-cell regulation. Hum Immunol. 2008;69:721–7. doi: 10.1016/j.humimm.2008.08.279. [DOI] [PubMed] [Google Scholar]
78.Fenoglio D, Ferrera F, Fravega M, et al. Advancements on phenotypic and functional characterization of non-antigen-specific CD8+ CD28− regulatory T cells. Hum Immunol. 2008;69:745–50. doi: 10.1016/j.humimm.2008.08.282. [DOI] [PubMed] [Google Scholar]
79.Chaput N, Louafi S, Bardier A, et al. Identification of CD8+ CD25+ Foxp3+ suppressive T cells in colorectal cancer tissue. Gut. 2009;58:520–9. doi: 10.1136/gut.2008.158824. [DOI] [PubMed] [Google Scholar]
80.Kiniwa Y, Miyahara Y, Wang HY, et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res. 2007;13:6947–58. doi: 10.1158/1078-0432.CCR-07-0842. [DOI] [PubMed] [Google Scholar]
81.Filaci G, Suciu-Foca N. CD8+ T suppressor cells are back to the game: are they players in autoimmunity? Autoimmun Rev. 2002;1:279–83. doi: 10.1016/s1568-9972(02)00065-4. [DOI] [PubMed] [Google Scholar]
82.Wei S, Kryczek I, Zou L, et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 2005;65:5020–6. doi: 10.1158/0008-5472.CAN-04-4043. [DOI] [PubMed] [Google Scholar]
83.Lu L, Yu Y, Li G, Pu L, Zhang F, Zheng S, Wang X. CD8+ CD103+ regulatory T cells in spontaneous tolerance of liver allografts. Int Immunopharmacol. 2009;9:546–8. doi: 10.1016/j.intimp.2009.01.021. [DOI] [PubMed] [Google Scholar]
84.Koch SD, Uss E, van Lier RA, ten Berge IJ. Alloantigen-induced regulatory CD8+ CD103+ T cells. Hum Immunol. 2008;69:737–44. doi: 10.1016/j.humimm.2008.08.281. [DOI] [PubMed] [Google Scholar]
85.Vlad G, Cortesini R, Suciu-Foca N. License to heal: bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC. J Immunol. 2005;174:5907–14. doi: 10.4049/jimmunol.174.10.5907. [DOI] [PubMed] [Google Scholar]
86.Vlad G, King J, Chang CC, Liu Z, Friedman RA, Torkamani AA, Suciu-Foca N. Gene profile analysis of CD8+ ILT3-Fc induced T suppressor cells. Hum Immunol. 2011;72:107–14. doi: 10.1016/j.humimm.2010.10.012. [DOI] [PubMed] [Google Scholar]
87.Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006;25:195–201. doi: 10.1016/j.immuni.2006.08.003. [DOI] [PubMed] [Google Scholar]
88.Colovai AI, Ciubotariu R, Liu Z, Cortesini R, Suciu-Foca N. CD8+ CD28− T suppressor cells represent a distinct subset in a heterogeneous population. Transplant Proc. 2001;33:104–7. doi: 10.1016/s0041-1345(00)01927-8. [DOI] [PubMed] [Google Scholar]
89.Chang CC, Liu Z, Vlad G, et al. Ig-like transcript 3 regulates expression of proinflammatory cytokines and migration of activated T cells. J Immunol. 2009;182:5208–16. doi: 10.4049/jimmunol.0804048. [DOI] [PubMed] [Google Scholar]
90.Filaci G, Fravega M, Fenoglio D, Rizzi M, Negrini S, Viggiani R, Indiveri F. Non-antigen specific CD8+ T suppressor lymphocytes. Clin Exp Med. 2004;4:86–92. doi: 10.1007/s10238-004-0042-3. [DOI] [PubMed] [Google Scholar]
91.Joly P, Guillon JM, Mayaud C, Plata F, Theodorou I, Denis M, Debre P, Autran B. Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes. J Immunol. 1989;143:2193–201. [PubMed] [Google Scholar]
92.Wang EC, Taylor-Wiedeman J, Perera P, Fisher J, Borysiewicz LK. Subsets of CD8+, CD57+ cells in normal, healthy individuals: correlations with human cytomegalovirus (HCMV) carrier status, phenotypic and functional analyses. Clin Exp Immunol. 1993;94:297–305. doi: 10.1111/j.1365-2249.1993.tb03447.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Tarazona R, Casado JG, Soto R, DelaRosa O, Peralbo E, Rioja L, Peña J, Solana R. Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword? Cancer Immunol Immunother. 2004;53:911–24. doi: 10.1007/s00262-004-0507-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
94.Henel G, Singh K, Cui D, Pryshchep S, Lee WW, Weyand CM, Goronzy JJ. Uncoupling of T-cell effector functions by inhibitory killer immunoglobulin-like receptors. Blood. 2006;107:4449–57. doi: 10.1182/blood-2005-06-2519. [DOI] [PMC free article] [PubMed] [Google Scholar]
95.Vivier E, Anfossi N. Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future. J Immunol. 2006;176:6121–9. doi: 10.1038/nri1306. [DOI] [PubMed] [Google Scholar]
96.Tarazona R, DelaRosa O, Alonso C, Ostos B, Espejo J, Peña J, Solana R. Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech Ageing Dev. 2000;121:77–88. doi: 10.1016/s0047-6374(00)00199-8. [DOI] [PubMed] [Google Scholar]
97.Warren HS, Rana PM, Rieger DT, Hewitt KA, Dahlstrom JE, Kent AL. CD8 T cells expressing killer Ig-like receptors and NKG2A are present in cord blood and express a more naïve phenotype than their counterparts in adult blood. J Leukoc Biol. 2006;79:1252–9. doi: 10.1189/jlb.0905536. [DOI] [PubMed] [Google Scholar]
98.Figueiredo C, Seltsam A, Blasczyk R. Permanent silencing of NKG2A expression for cell-based therapeutics. J Mol Med. 2009;87:199–210. doi: 10.1007/s00109-008-0417-0. [DOI] [PubMed] [Google Scholar]
99.Natarajan K, Dimasi N, Wang J, Mariuzza RA, Margulies DH. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol. 2002;20:853–85. doi: 10.1146/annurev.immunol.20.100301.064812. [DOI] [PubMed] [Google Scholar]
100.Ibegbu CC, Xu YX, Harris W, Maggio D, Miller JD, Kourtis AP. Expression of killer cell lectin-like receptor G1 on antigen-specific human CD8+ T lymphocytes during active, latent, and resolved infection and its relation with CD57. J Immunol. 2005;174:6088–94. doi: 10.4049/jimmunol.174.10.6088. [DOI] [PubMed] [Google Scholar]
101.Simpson RJ. Aging, persistent viral infections, and immunosenescence: can exercise “make space”? Exerc Sport Sci Rev. 2011;39:23–33. doi: 10.1097/JES.0b013e318201f39d. [DOI] [PubMed] [Google Scholar]
102.Blackburn SD, Crawford A, Shin H, Polley A, Freeman GJ, Wherry EJ. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J Virol. 2010;84:2078–89. doi: 10.1128/JVI.01579-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
103.Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–45. doi: 10.1038/ni1443. [DOI] [PubMed] [Google Scholar]
104.Khaitan A, Unutmaz D. Revisiting immune exhaustion during HIV infection. Curr HIV/AIDS Rep. 2011;8:4–11. doi: 10.1007/s11904-010-0066-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634–43. doi: 10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
106.Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8. doi: 10.1038/85330. [DOI] [PubMed] [Google Scholar]
107.Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, Sharpe AH. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol. 2003;33:2706–16. doi: 10.1002/eji.200324228. [DOI] [PubMed] [Google Scholar]
108.Sauce D, Almeida JR, Larsen M, Haro L, Autran B, Freeman GJ, Appay V. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS. 2007;21:2005–13. doi: 10.1097/QAD.0b013e3282eee548. [DOI] [PubMed] [Google Scholar]
109.Effros RB, Boucher N, Porter V, et al. Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol. 1994;29:601–9. doi: 10.1016/0531-5565(94)90073-6. [DOI] [PubMed] [Google Scholar]
110.Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schächter F. CD28 expression in T cell aging and human longevity. Exp Gerontol. 1998;33:267–82. doi: 10.1016/s0531-5565(97)00132-0. [DOI] [PubMed] [Google Scholar]
111.Looney RJ, Falsey A, Campbell D, et al. Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol. 1999;90:213–9. doi: 10.1006/clim.1998.4638. [DOI] [PubMed] [Google Scholar]
112.Fagnoni FF, Vescovini R, Mazzola M, et al. Expansion of cytotoxic CD8++ CCD28− T cells in healthy ageing people, including centenarians. Immunology. 1996;88:501–7. doi: 10.1046/j.1365-2567.1996.d01-689.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O'Fallon WM, Weyand CM. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol. 2001;75:12182–7. doi: 10.1128/JVI.75.24.12182-12187.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Saurwein-Teissl M, Lung TL, Marx F, et al. Lack of antibody production following immunization in old age: association with CD8+ CD28− T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol. 2002;168:5893–9. doi: 10.4049/jimmunol.168.11.5893. [DOI] [PubMed] [Google Scholar]
115.Trzonkowski P, Myśliwska J, Szmit E, Wieckiewicz J, Lukaszuk K, Brydak LB, Machała M, Myśliwski A. Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination – an impact of immunosenescence. Vaccine. 2003;21:3826–36. doi: 10.1016/s0264-410x(03)00309-8. [DOI] [PubMed] [Google Scholar]
116.Focosi D, Petrini M. CD57 expression on lymphoma microenvironment as a new prognostic marker related to immune dysfunction. J Clin Oncol. 2007;25:1289–91. doi: 10.1200/JCO.2006.10.2251. [DOI] [PubMed] [Google Scholar]
117.Wikby A, Ferguson F, Forsey R, et al. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci. 2005;60:556–65. doi: 10.1093/gerona/60.5.556. [DOI] [PubMed] [Google Scholar]
118.Simpson RJ, Cosgrove C, Chee MM, et al. Senescent phenotypes and telomere lengths of peripheral blood T-cells mobilized by acute exercise in humans. Exerc Immunol Rev. 2010;16:40–55. [PubMed] [Google Scholar]
119.Turner JE, Aldred S, Witard OC, Drayson MT, Moss PM, Bosch JA. Latent cytomegalovirus infection amplifies CD8 T-lymphocyte mobilisation and egress in response to exercise. Brain Behav Immun. 2010;24:1362–70. doi: 10.1016/j.bbi.2010.07.239. [DOI] [PubMed] [Google Scholar]
120.Meloni F, Morosini M, Solari N, et al. Foxp3 expressing CD4+ CD25+ and CD8+ CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum Immunol. 2006;67:1–12. doi: 10.1016/j.humimm.2005.11.005. [DOI] [PubMed] [Google Scholar]
121.Characiejus D, Pasukoniene V, Jonusauskaite R, Azlauskaite N, Aleknavicius E, Mauricas M, Otter WD. Peripheral blood CD8high CD57+ lymphocyte levels may predict outcome in melanoma patients treated with adjuvant interferon-alpha. Anticancer Res. 2008;28:1139–42. [PubMed] [Google Scholar]
122.Characiejus D, Pasukoniene V, Kazlauskaite N, Valuckas KP, Petraitis T, Mauricas M, Den Otter W. Predictive value of CD8high CD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. Anticancer Res. 2002;22:3679–83. [PubMed] [Google Scholar]
123.Characiejus D, Pasukoniene V, Jacobs JJ, et al. Prognostic significance of peripheral blood CD8high CD57+ lymphocytes in bladder carcinoma patients after intravesical IL-2. Anticancer Res. 2011;31:699–703. [PubMed] [Google Scholar]
124.Okada T, Iiai T, Kawachi Y, Moroda T, Takii Y, Hatakeyama K, Abo T. Origin of CD57+ T cells which increase at tumour sites in patients with colorectal cancer. Clin Exp Immunol. 1995;102:159–66. doi: 10.1111/j.1365-2249.1995.tb06650.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Serrano D, Monteiro J, Allen SL, et al. Clonal expansion within the CD4+ CD57+ and CD8+ CD57+ T cell subsets in chronic lymphocytic leukemia. J Immunol. 1997;158:1482–9. [PubMed] [Google Scholar]
126.Vidriales MB, Orfao A, López-Berges MC, et al. Lymphoid subsets in acute myeloid leukemias: increased number of cells with NK phenotype and normal T-cell distribution. Ann Hematol. 1993;67:217–22. doi: 10.1007/BF01715050. [DOI] [PubMed] [Google Scholar]
127.Kook H, Zeng W, Guibin C, Kirby M, Young NS, Maciejewski JP. Increased cytotoxic T cells with effector phenotype in aplastic anemia and myelodysplasia. Exp Hematol. 2001;29:1270–7. doi: 10.1016/s0301-472x(01)00736-6. [DOI] [PubMed] [Google Scholar]
128.Dondi E, Roué G, Yuste VJ, Susin SA, Pellegrini S. A dual role of IFN-alpha in the balance between proliferation and death of human CD4+ T lymphocytes during primary response. J Immunol. 2004;173:3740–7. doi: 10.4049/jimmunol.173.6.3740. [DOI] [PubMed] [Google Scholar]
129.Characiejus D, Hodzic J, Jacobs JJ. “First do no harm” and the importance of prediction in oncology. EPMA J. 2010;1:369–75. doi: 10.1007/s13167-010-0042-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
130.Labalette M, Salez F, Pruvot FR, Noel C, Dessaint JP. CD8 lymphocytosis in primary cytomegalovirus (CMV) infection of allograft recipients: expansion of an uncommon CD8+ CD57− subset and its progressive replacement by CD8+ CD57+ T cells. Clin Exp Immunol. 1994;95:465–71. doi: 10.1111/j.1365-2249.1994.tb07020.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Wallace DL, Masters JE, De Lara CM, et al. Human cytomegalovirus-specific CD8+ T-cell expansions contain long-lived cells that retain functional capacity in both young and elderly subjects. Immunology. 2011;132:27–38. doi: 10.1111/j.1365-2567.2010.03334.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Petrova M, Muhtarova M, Nikolova M, Magaev S, Taskov H, Nikolovska D, Krastev Z. Chronic Epstein–Barr virus-related hepatitis in immunocompetent patients. World J Gastroenterol. 2006;12:5711–6. doi: 10.3748/wjg.v12.i35.5711. [DOI] [PMC free article] [PubMed] [Google Scholar]
133.Manfras BJ, Weidenbach H, Beckh KH, Kern P, Möller P, Adler G, Mertens T, Boehm BO. Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy. J Clin Immunol. 2004;24:258–71. doi: 10.1023/B:JOCI.0000025447.23473.ab. [DOI] [PubMed] [Google Scholar]
134.Isa A, Kasprowicz V, Norbeck O, et al. Prolonged activation of virus-specific CD8+ T cells after acute B19 infection. PLoS Med. 2005;2:e343. doi: 10.1371/journal.pmed.0020343. [DOI] [PMC free article] [PubMed] [Google Scholar]
135.Aronsson B, Troye-Blomberg M, Smedman L. Increase of circulating CD8+ CD57+ lymphocytes after measles infection but not after measles vaccination. J Clin Lab Immunol. 2004;53:1–12. –2005. [PubMed] [Google Scholar]
136.Kaplan RC, Sinclair E, Landay AL, et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis. 2011;203:452–63. doi: 10.1093/infdis/jiq071. [DOI] [PMC free article] [PubMed] [Google Scholar]
137.Cao W, Jamieson BD, Hultin LE, Hultin PM, Effros RB, Detels R. Premature aging of T cells is associated with faster HIV-1 disease progression. J Acquir Immune Defic Syndr. 2009;50:137–47. doi: 10.1097/QAI.0b013e3181926c28. [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Scheinberg P, Melenhorst JJ, Brenchley JM, et al. The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. Blood. 2009;114:5071–80. doi: 10.1182/blood-2009-04-214684. [DOI] [PMC free article] [PubMed] [Google Scholar]
139.Bernal-Fernandez G, Espinosa-Cueto P, Leyva-Meza R, Mancilla N, Mancilla R. Decreased expression of T-cell costimulatory molecule CD28 on CD4 and CD8 T cells of Mexican patients with pulmonary tuberculosis. Tuberculosis Research and Treatment. 2010;2010:517547. doi: 10.1155/2010/517547. DOI: 10.1155/2010/517547. [DOI] [PMC free article] [PubMed] [Google Scholar]
140.Stricker RB, Burrascano J, Winger E. Longterm decrease in the CD57 lymphocyte subset in a patient with chronic Lyme disease. Ann Agric Environ Med. 2002;9:111–3. [PubMed] [Google Scholar]
141.Wang EC, Lawson TM, Vedhara K, Moss PA, Lehner PJ, Borysiewicz LK. CD8high+CD57+ T cells in patients with rheumatoid arthritis. Arthritis Rheum. 1997;40:237–48. doi: 10.1002/art.1780400208. [DOI] [PubMed] [Google Scholar]
142.Fasth AE, Dastmalchi M, Rahbar A, et al. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. J Immunol. 2009;183:4792–9. doi: 10.4049/jimmunol.0803688. [DOI] [PubMed] [Google Scholar]
143.Scarsi M, Ziglioli T, Airò P. Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response. J Rheumatol. 2010;37:911–6. doi: 10.3899/jrheum.091176. [DOI] [PubMed] [Google Scholar]
144.Klaus G, Mostert K, Reckzeh B, Mueller TF. Phenotypic changes in lymphocyte subpopulations in pediatric renal-transplant patients after T-cell depletion. Transplantation. 2003;76:1719–24. doi: 10.1097/01.TP.0000100396.81490.0C. [DOI] [PubMed] [Google Scholar]
145.Vlad G, Cortesini R, Suciu-Foca N. CD8+ T suppressor cells and the ILT3 master switch. Hum Immunol. 2008;69:681–6. doi: 10.1016/j.humimm.2008.08.286. [DOI] [PubMed] [Google Scholar]
146.Suciu-Foca N, Cortesini R. Central role of ILT3 in the T suppressor cell cascade. Cell Immunol. 2007;248:59–67. doi: 10.1016/j.cellimm.2007.01.013. [DOI] [PubMed] [Google Scholar]
147.Song K, Coleman RA, Alber C, Ballas ZK, Waldschmidt TJ, Mortari F, LaBrecque DR, Cook RT. TH1 cytokine response of CD57+ T-cell subsets in healthy controls and patients with alcoholic liver disease. Alcohol. 2001;24:155–67. doi: 10.1016/s0741-8329(01)00146-x. [DOI] [PubMed] [Google Scholar]
148.Olloquequi J, Montes JF, Prats A, Rodríguez E, Montero MA, García-Valero J, Ferrer J. Significant increase of CD57+ cells in pulmonary lymphoid follicles of COPD patients. Eur Respir J. 2011;37:289–98. doi: 10.1183/09031936.00201509. [DOI] [PubMed] [Google Scholar]
149.Sharma G, Hanania NA, Shim YM. The aging immune system and its relationship to the development of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6:573–80. doi: 10.1513/pats.200904-022RM. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b1] 1.Nagata T, Koide Y. Induction of specific CD8 T cells against intracellular bacteria by CD8 T-cell-oriented immunization approaches. J Biomed Biotechnol. 2010;2010:764542. doi: 10.1155/2010/764542. DOI: 10.1155/2010/764542. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b2] 2.Tsukishiro T, Donnenberg AD, Whiteside TL. Rapid turnover of the CD8+ CD28− T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol Immunother. 2003;52:599–607. doi: 10.1007/s00262-003-0395-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b3] 3.Arosa FA. CD8+ CD28− T cells: certainties and uncertainties of a prevalent human T-cell subset. Immunol Cell Biol. 2002;80:1–13. doi: 10.1046/j.1440-1711.2002.01057.x. [DOI] [PubMed] [Google Scholar]

[b4] 4.Bernard A, Lamy L, Alberti I. The two-signal model of T-cell activation after 30 years. Transplantation. 2002;73:S31–5. doi: 10.1097/00007890-200201151-00011. [DOI] [PubMed] [Google Scholar]

[b5] 5.Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158–69. doi: 10.1111/j.0105-2896.2005.00256.x. [DOI] [PubMed] [Google Scholar]

[b6] 6.Boesteanu AC, Katsikis PD. Memory T cells need CD28 costimulation to remember. Semin Immunol. 2009;21:69–77. doi: 10.1016/j.smim.2009.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b7] 7.Brenchley JM, Karandikar NJ, Betts MR, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101:2711–20. doi: 10.1182/blood-2002-07-2103. [DOI] [PubMed] [Google Scholar]

[b8] 8.Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol. 2002;2:251–62. doi: 10.1038/nri778. [DOI] [PubMed] [Google Scholar]

[b9] 9.Merino J, Martínez-González MA, Rubio M, Inogés S, Sánchez-Ibarrola A, Subirá ML. Progressive decrease of CD8high+ CD28+ CD57− cells with ageing. Clin Exp Immunol. 1998;112:48–51. doi: 10.1046/j.1365-2249.1998.00551.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b10] 10.Bandrés E, Merino J, Vázquez B, Inogés S, Moreno C, Subirá ML, Sánchez-Ibarrola A. The increase of IFN-gamma production through aging correlates with the expanded CD8+high CD28− CD57+ subpopulation. Clin Immunol. 2000;96:230–5. doi: 10.1006/clim.2000.4894. [DOI] [PubMed] [Google Scholar]

[b11] 11.Focosi D, Bestagno M, Burrone O, Petrini M. CD57+ T lymphocytes and functional immune deficiency. J Leukoc Biol. 2010;87:107–16. doi: 10.1189/jlb.0809566. [DOI] [PubMed] [Google Scholar]

[b12] 12.Uusitalo M, Kivelä T. The HNK-1 carbohydrate epitope in the eye: basic science and functional implications. Prog Retin Eye Res. 2001;20:1–28. doi: 10.1016/s1350-9462(00)00018-5. [DOI] [PubMed] [Google Scholar]

[b13] 13.Valenzuela HF, Effros RB. Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol. 2002;105:117–25. doi: 10.1006/clim.2002.5271. [DOI] [PubMed] [Google Scholar]

[b14] 14.Unemori P, Hunt P, Leslie K, Sinclair E, Deeks S, Martin J, Maurer T. CD57+, a global marker of immunosenescence, is elevated in an atypical cohort of patients with Kaposi sarcoma and well-controlled HIV. Infect Agent Cancer. 2009;4:P43. [Google Scholar]

[b15] 15.Weng NP, Akbar AN, Goronzy J. CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30:306–12. doi: 10.1016/j.it.2009.03.013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b16] 16.Abedin S, Michel JJ, Lemster B, Vallejo AN. Diversity of NKR expression in aging T cells and in T cells of the aged: the new frontier into the exploration of protective immunity in the elderly. Exp Gerontol. 2005;40:537–48. doi: 10.1016/j.exger.2005.04.012. [DOI] [PubMed] [Google Scholar]

[b17] 17.Nadareishvili ZG, Li H, Wright V, et al. Elevated pro-inflammatory CD4+ CD28− lymphocytes and stroke recurrence and death. Neurology. 2004;63:1446–51. doi: 10.1212/01.wnl.0000142260.61443.7c. [DOI] [PubMed] [Google Scholar]

[b18] 18.Appay V, Rowland-Jones SL. Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol. 2004;16:205–12. doi: 10.1016/j.smim.2004.02.007. [DOI] [PubMed] [Google Scholar]

[b19] 19.Ben-David H, Sharabi A, Dayan M, Sela M, Mozes E. The role of CD8+ CD28− regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand. Proc Natl Acad Sci USA. 2007;104:17459–64. doi: 10.1073/pnas.0708577104. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b20] 20.Ménager-Marcq I, Pomié C, Romagnoli P, van Meerwijk JP. CD8+ CD28− regulatory T lymphocytes prevent experimental inflammatory bowel disease in mice. Gastroenterology. 2006;131:1775–85. doi: 10.1053/j.gastro.2006.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b21] 21.Ortiz-Suárez A, Miller RA. A subset of CD8 memory T cells from old mice have high levels of CD28 and produce IFN-gamma. Clin Immunol. 2002;104:282–92. doi: 10.1006/clim.2002.5221. [DOI] [PubMed] [Google Scholar]

[b22] 22.Sze DM, Giesajtis G, Brown RD, et al. Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8+ CD57+ CD28− compartment. Blood. 2001;98:2817–27. doi: 10.1182/blood.v98.9.2817. [DOI] [PubMed] [Google Scholar]

[b23] 23.Jennings C, Rich K, Siegel JN, Landay A. A phenotypic study of CD8+ lymphocyte subsets in infants using three-color flow cytometry. Clin Immunol Immunopathol. 1994;71:8–13. doi: 10.1006/clin.1994.1044. [DOI] [PubMed] [Google Scholar]

[b24] 24.Weekes MP, Wills MR, Mynard K, Hicks R, Sissons JG, Carmichael AJ. Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28− CD8+ T-cell population. Immunology. 1999;98:443–9. doi: 10.1046/j.1365-2567.1999.00901.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b25] 25.Fiorentini S, Malacarne F, Ricotta D, et al. Generation of CD28− cells from long-term-stimulated CD8+ CD28+ T cells: a possible mechanism accounting for the increased number of CD8+ CD28− T cells in HIV-1-infected patients. J Leukoc Biol. 1999;65:641–8. doi: 10.1002/jlb.65.5.641. [DOI] [PubMed] [Google Scholar]

[b26] 26.Labalette M, Leteurtre E, Thumerelle C, Grutzmacher C, Tourvieille B, Dessaint JP. Peripheral human CD8+ CD28+ T lymphocytes give rise to CD28− progeny, but IL-4 prevents loss of CD28 expression. Int Immunol. 1999;11:1327–36. doi: 10.1093/intimm/11.8.1327. [DOI] [PubMed] [Google Scholar]

[b27] 27.Lazuardi L, Herndler-Brandstetter D, Brunner S, Laschober GT, Lepperdinger G, Grubeck-Loebenstein B. Microarray analysis reveals similarity between CD8+ CD28− T cells from young and elderly persons, but not of CD8+ CD28+ T cells. Biogerontology. 2009;10:191–202. doi: 10.1007/s10522-008-9167-1. [DOI] [PubMed] [Google Scholar]

[b28] 28.Vivar N, Thang PH, Atlas A, Chiodi F, Rethi B. Potential role of CD8+ CD28− T lymphocytes in immune activation during HIV-1 infection. AIDS. 2008;22:1083–6. doi: 10.1097/QAD.0b013e3282fce613. [DOI] [PubMed] [Google Scholar]

[b29] 29.Fateminasab FD, Shahgasempour S, Mirsaeidi SM, Tabarsi P, Mansoori SD, Entezami Z. Increased activation and expansion of a CD57+ subset within peripheral CD8+ T lymphocytes in Mycobacterium tuberculosis-infected patients. Arch Iran Med. 2006;9:53–7. [PubMed] [Google Scholar]

[b30] 30.García-Muñoz R, Rodríguez-Otero P, Galar A, Merino J, Beunza JJ, Páramo JA, Lecumberri R. Expansion of CD8+ CD57+ T cells in an immunocompetent patient with acute toxoplasmosis. Adv Hematol. 2009;209:173439. doi: 10.1155/2009/173439. DOI: 10.1155/2009/173439. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b31] 31.Le Priol Y, Puthier D, Lécureuil C, Combadière C, Debré P, Nguyen C, Combadière B. High cytotoxic and specific migratory potencies of senescent CD8+ CD57+ cells in HIV-infected and uninfected individuals. J Immunol. 2006;177:5145–54. doi: 10.4049/jimmunol.177.8.5145. [DOI] [PubMed] [Google Scholar]

[b32] 32.Sada-Ovalle I, Torre-Bouscoulet L, Valdez-Vázquez R, Martínez-Cairo S, Zenteno E, Lascurain R. Characterization of a cytotoxic CD57+ T cell subset from patients with pulmonary tuberculosis. Clin Immunol. 2006;121:314–23. doi: 10.1016/j.clim.2006.08.011. [DOI] [PubMed] [Google Scholar]

[b33] 33.Wood KL, Voss OH, Huang Q, Parihar A, Mehta N, Batra S, Doseff AI. The small heat shock protein 27 is a key regulator of CD8+ CD57+ lymphocyte survival. J Immunol. 2010;184:5582–8. doi: 10.4049/jimmunol.0902953. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b34] 34.Mollet L, Sadat-Sowti B, Duntze J, et al. CD8hi+ CD57+ T lymphocytes are enriched in antigen-specific T cells capable of down-modulating cytotoxic activity. Int Immunol. 1998;10:311–23. doi: 10.1093/intimm/10.3.311. [DOI] [PubMed] [Google Scholar]

[b35] 35.Mendes AV, Kallas EG, Benard G, et al. Impact of cytomegalovirus and grafts versus host disease on the dynamics of CD57+ CD28− CD8+ T cells after bone marrow transplant. Clinics (Sao Paulo) 2008;63:667–76. doi: 10.1590/S1807-59322008000500016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b36] 36.Weinberger B, Welzl K, Herndler-Brandstetter D, Parson W, Grubeck-Loebenstein B. CD28− CD8+ T cells do not contain unique clonotypes and are therefore dispensable. Immunol Lett. 2009;127:27–32. doi: 10.1016/j.imlet.2009.08.008. [DOI] [PubMed] [Google Scholar]

[b37] 37.Dunne PJ, Faint JM, Gudgeon NH, et al. Epstein–Barr virus-specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood. 2002;100:933–40. doi: 10.1182/blood-2002-01-0160. [DOI] [PubMed] [Google Scholar]

[b38] 38.Effros RB. Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. Exp Gerontol. 2011;46:135–40. doi: 10.1016/j.exger.2010.08.027. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b39] 39.Plunkett FJ, Franzese O, Finney HM, et al. The loss of telomerase activity in highly differentiated CD8+ CD28− CD27− T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007;178:7710–9. doi: 10.4049/jimmunol.178.12.7710. [DOI] [PubMed] [Google Scholar]

[b40] 40.Chong LK, Aicheler RJ, Llewellyn-Lacey S, Tomasec P, Brennan P, Wang EC. Proliferation and interleukin 5 production by CD8hi CD57+ T cells. Eur J Immunol. 2008;38:995–1000. doi: 10.1002/eji.200737687. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b41] 41.Chiu WK, Fann M, Weng NP. Generation and growth of CD28null CD8+ memory T cells mediated by IL-15 and its induced cytokines. J Immunol. 2006;177:7802–10. doi: 10.4049/jimmunol.177.11.7802. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b42] 42.Kober J, Leitner J, Klauser C, et al. The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells. Eur J Immunol. 2008;38:2678–88. doi: 10.1002/eji.200838250. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b43] 43.Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40. doi: 10.1038/nrm2233. [DOI] [PubMed] [Google Scholar]

[b44] 44.Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192:547–56. doi: 10.1083/jcb.201009094. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b45] 45.von Zglinicki T, Saretzki G, Ladhoff J, d'Adda di Fagagna F, Jackson SP. Human cell senescence as a DNA damage response. Mech Ageing Dev. 2005;126:111–7. doi: 10.1016/j.mad.2004.09.034. [DOI] [PubMed] [Google Scholar]

[b46] 46.Appay V, Papagno L, Spina CA, et al. Dynamics of T cell responses in HIV infection. J Immunol. 2002;168:3660–6. doi: 10.4049/jimmunol.168.7.3660. [DOI] [PubMed] [Google Scholar]

[b47] 47.Papagno L, Spina CA, Marchant A, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol. 2004;2:0173–85. doi: 10.1371/journal.pbio.0020020. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b48] 48.Henson SM, Franzese O, Macaulay R, et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood. 2009;113:6619–28. doi: 10.1182/blood-2009-01-199588. [DOI] [PubMed] [Google Scholar]

[b49] 49.Borthwick NJ, Lowdell M, Salmon M, Akbar AN. Loss of CD28 expression on CD8+ T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol. 2000;12:1005–13. doi: 10.1093/intimm/12.7.1005. [DOI] [PubMed] [Google Scholar]

[b50] 50.Wood KL, Twigg HL, 3rd, Doseff AI. Dysregulation of CD8+ lymphocyte apoptosis, chronic disease, and immune regulation. Front Biosci. 2009;14:3771–81. doi: 10.2741/3487. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b51] 51.Effros RB. Replicative senescence of CD8 T cells: potential effects on cancer immune surveillance and immunotherapy. Cancer Immunol Immunother. 2004;53:925–33. doi: 10.1007/s00262-004-0508-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b52] 52.Spaulding C, Guo W, Effros RB. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol. 1999;34:633–44. doi: 10.1016/s0531-5565(99)00033-9. [DOI] [PubMed] [Google Scholar]

[b53] 53.Strauss G, Knape I, Melzner I, Debatin KM. Constitutive caspase activation and impaired death-inducing signaling complex formation in CD95-resistant, long-term activated, antigen-specific T cells. J Immunol. 2003;171:1172–82. doi: 10.4049/jimmunol.171.3.1172. [DOI] [PubMed] [Google Scholar]

[b54] 54.Wood KL, Knox KS, Wang Y, Day RB, Schnizlein-Bick C, Twigg HL., 3rd Apoptosis of CD57+ and CD57− lymphocytes in the lung and blood of HIV-infected subjects. Clin Immunol. 2005;117:294–301. doi: 10.1016/j.clim.2005.09.009. [DOI] [PubMed] [Google Scholar]

[b55] 55.Salminen A, Ojala J, Kaarniranta K. Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cell Mol Life Sci. 2011;68:1021–31. doi: 10.1007/s00018-010-0597-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b56] 56.Suciu-Foca N, Manavalan JS, Scotto L, et al. Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. Int Immunopharmacol. 2005;5:7–11. doi: 10.1016/j.intimp.2004.09.003. [DOI] [PubMed] [Google Scholar]

[b57] 57.Urbaniak-Kujda D, Kapelko-Słowik K, Wołowiec D, et al. Increased percentage of CD8+ CD28− suppressor lymphocytes in peripheral blood and skin infiltrates correlates with advanced disease in patients with cutaneous T-cell lymphomas. Postepy Hig Med Dosw (Online) 2009;63:355–9. [PubMed] [Google Scholar]

[b58] 58.Filaci G, Fenoglio D, Fravega M, et al. CD8+ CD28− T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol. 2007;179:4323–34. doi: 10.4049/jimmunol.179.7.4323. [DOI] [PubMed] [Google Scholar]

[b59] 59.Lin YX, Wang LL, Yan LN, Cai P, Li B, Wen TF, Zeng Y. Analysis of CD8+ CD28− T-suppressor cells in living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2009;8:241–6. [PubMed] [Google Scholar]

[b60] 60.Tulunay A, Yavuz S, Direskeneli H, Eksioglu-Demiralp E. CD8+ CD28−, suppressive T cells in systemic lupus erythematosus. Lupus. 2008;17:630–7. doi: 10.1177/0961203308089400. [DOI] [PubMed] [Google Scholar]

[b61] 61.Mikulkova Z, Praksova P, Stourac P, et al. Numerical defects in CD8+ CD28− T-suppressor lymphocyte population in patients with type 1 diabetes mellitus and multiple sclerosis. Cell Immunol. 2010;262:75–9. doi: 10.1016/j.cellimm.2010.02.002. [DOI] [PubMed] [Google Scholar]

[b62] 62.Sun Z, Zhong W, Lu X, Shi B, Zhu Y, Chen L, Zhang G, Zhang X. Association of Graves’ disease and prevalence of circulating IFN-gamma-producing CD28− T cells. J Clin Immunol. 2008;28:464–72. doi: 10.1007/s10875-008-9213-4. [DOI] [PubMed] [Google Scholar]

[b63] 63.Fiorentino S, Dalod M, Olive D, Guillet JG, Gomard E. Predominant involvement of CD8+ CD28− lymphocytes in human immunodeficiency virus-specific cytotoxic activity. J Virol. 1996;70:2022–6. doi: 10.1128/jvi.70.3.2022-2026.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b64] 64.Schirmer M, Goldberger C, Würzner R, Duftner C, Pfeiffer KP, Clausen J, Neumayr G, Falkenbach A. Circulating cytotoxic CD8+ CD28− T cells in ankylosing spondylitis. Arthritis Res. 2002;4:71–6. doi: 10.1186/ar386. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b65] 65.Hamzaoui A, Chaouch N, Grairi H, Ammar J, Hamzaoui K. Inflammatory process of CD8+ CD28− T cells in induced sputum from asthmatic patients. Mediators Inflamm. 2005;2005:160–6. doi: 10.1155/MI.2005.160. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b66] 66.Ohkawa T, Seki S, Dobashi H, Koike Y, Habu Y, Ami K, Hiraide H, Sekine I. Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology. 2001;103:281–90. doi: 10.1046/j.1365-2567.2001.01248.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b67] 67.Pedroza-Seres M, Linares M, Voorduin S, Enrique RR, Lascurain R, Garfias Y, Jimenez-Martinez MC. Pars planitis is associated with an increased frequency of effector-memory CD57+ T cells. Br J Ophthalmol. 2007;91:1393–8. doi: 10.1136/bjo.2007.116277. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b68] 68.Chattopadhyay PK, Betts MR, Price DA, Gostick E, Horton H, Roederer M, De Rosa SC. The cytolytic enzymes granzyme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression. J Leukoc Biol. 2009;85:88–97. doi: 10.1189/jlb.0208107. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b69] 69.Frassanito MA, Silvestris F, Cafforio P, Dammacco F. CD8+/CD57+ cells and apoptosis suppress T-cell functions in multiple myeloma. Br J Haematol. 1998;100:469–77. doi: 10.1046/j.1365-2141.1998.00589.x. [DOI] [PubMed] [Google Scholar]

[b70] 70.Gorochov G, Debré P, Leblond V, Sadat-Sowti B, Sigaux F, Autran B. Oligoclonal expansion of CD8+ CD57+ T cells with restricted T-cell receptor beta chain variability after bone marrow transplantation. Blood. 1994;83:587–95. [PubMed] [Google Scholar]

[b71] 71.Sadat-Sowti B, Debré P, Mollet L, Quint L, Hadida F, Leblond V, Bismuth G, Autran B. An inhibitor of cytotoxic functions produced by CD8+ CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients. Eur J Immunol. 1994;24:2882–8. doi: 10.1002/eji.1830241145. [DOI] [PubMed] [Google Scholar]

[b72] 72.Casado JG, Soto R, DelaRosa O, et al. CD8 T cells expressing NK associated receptors are increased in melanoma patients and display an effector phenotype. Cancer Immunol Immunother. 2005;54:1162–71. doi: 10.1007/s00262-005-0682-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b73] 73.Dolstra H, Preijers F, Van de Wiel-van Kemenade E, Schattenberg A, Galama J, de Witte T. Expansion of CD8+ CD57+ T cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection. Br J Haematol. 1995;90:300–7. doi: 10.1111/j.1365-2141.1995.tb05150.x. [DOI] [PubMed] [Google Scholar]

[b74] 74.Eylar EH, Lefranc CE, Yamamura Y, Báez I, Colón-Martinez SL, Rodriguez N, Breithaupt TB. HIV infection and aging: enhanced Interferon- and Tumor Necrosis Factor-alpha production by the CD8+ CD28− T subset. BMC Immunol. 2001;2:10. doi: 10.1186/1471-2172-2-10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b75] 75.Wenzel SE. Eosinophils in asthma – closing the loop or opening the door? N Engl J Med. 2009;360:1026–8. doi: 10.1056/NEJMe0900334. [DOI] [PubMed] [Google Scholar]

[b76] 76.Chess L, Jiang H. Resurrecting CD8+ suppressor T cells. Nat Immunol. 2004;5:469–71. doi: 10.1038/ni0504-469. [DOI] [PubMed] [Google Scholar]

[b77] 77.Jiang H, Chess L. Qa-1/HLA-E-restricted regulatory CD8+ T cells and self-nonself discrimination: an essay on peripheral T-cell regulation. Hum Immunol. 2008;69:721–7. doi: 10.1016/j.humimm.2008.08.279. [DOI] [PubMed] [Google Scholar]

[b78] 78.Fenoglio D, Ferrera F, Fravega M, et al. Advancements on phenotypic and functional characterization of non-antigen-specific CD8+ CD28− regulatory T cells. Hum Immunol. 2008;69:745–50. doi: 10.1016/j.humimm.2008.08.282. [DOI] [PubMed] [Google Scholar]

[b79] 79.Chaput N, Louafi S, Bardier A, et al. Identification of CD8+ CD25+ Foxp3+ suppressive T cells in colorectal cancer tissue. Gut. 2009;58:520–9. doi: 10.1136/gut.2008.158824. [DOI] [PubMed] [Google Scholar]

[b80] 80.Kiniwa Y, Miyahara Y, Wang HY, et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res. 2007;13:6947–58. doi: 10.1158/1078-0432.CCR-07-0842. [DOI] [PubMed] [Google Scholar]

[b81] 81.Filaci G, Suciu-Foca N. CD8+ T suppressor cells are back to the game: are they players in autoimmunity? Autoimmun Rev. 2002;1:279–83. doi: 10.1016/s1568-9972(02)00065-4. [DOI] [PubMed] [Google Scholar]

[b82] 82.Wei S, Kryczek I, Zou L, et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 2005;65:5020–6. doi: 10.1158/0008-5472.CAN-04-4043. [DOI] [PubMed] [Google Scholar]

[b83] 83.Lu L, Yu Y, Li G, Pu L, Zhang F, Zheng S, Wang X. CD8+ CD103+ regulatory T cells in spontaneous tolerance of liver allografts. Int Immunopharmacol. 2009;9:546–8. doi: 10.1016/j.intimp.2009.01.021. [DOI] [PubMed] [Google Scholar]

[b84] 84.Koch SD, Uss E, van Lier RA, ten Berge IJ. Alloantigen-induced regulatory CD8+ CD103+ T cells. Hum Immunol. 2008;69:737–44. doi: 10.1016/j.humimm.2008.08.281. [DOI] [PubMed] [Google Scholar]

[b85] 85.Vlad G, Cortesini R, Suciu-Foca N. License to heal: bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC. J Immunol. 2005;174:5907–14. doi: 10.4049/jimmunol.174.10.5907. [DOI] [PubMed] [Google Scholar]

[b86] 86.Vlad G, King J, Chang CC, Liu Z, Friedman RA, Torkamani AA, Suciu-Foca N. Gene profile analysis of CD8+ ILT3-Fc induced T suppressor cells. Hum Immunol. 2011;72:107–14. doi: 10.1016/j.humimm.2010.10.012. [DOI] [PubMed] [Google Scholar]

[b87] 87.Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006;25:195–201. doi: 10.1016/j.immuni.2006.08.003. [DOI] [PubMed] [Google Scholar]

[b88] 88.Colovai AI, Ciubotariu R, Liu Z, Cortesini R, Suciu-Foca N. CD8+ CD28− T suppressor cells represent a distinct subset in a heterogeneous population. Transplant Proc. 2001;33:104–7. doi: 10.1016/s0041-1345(00)01927-8. [DOI] [PubMed] [Google Scholar]

[b89] 89.Chang CC, Liu Z, Vlad G, et al. Ig-like transcript 3 regulates expression of proinflammatory cytokines and migration of activated T cells. J Immunol. 2009;182:5208–16. doi: 10.4049/jimmunol.0804048. [DOI] [PubMed] [Google Scholar]

[b90] 90.Filaci G, Fravega M, Fenoglio D, Rizzi M, Negrini S, Viggiani R, Indiveri F. Non-antigen specific CD8+ T suppressor lymphocytes. Clin Exp Med. 2004;4:86–92. doi: 10.1007/s10238-004-0042-3. [DOI] [PubMed] [Google Scholar]

[b91] 91.Joly P, Guillon JM, Mayaud C, Plata F, Theodorou I, Denis M, Debre P, Autran B. Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes. J Immunol. 1989;143:2193–201. [PubMed] [Google Scholar]

[b92] 92.Wang EC, Taylor-Wiedeman J, Perera P, Fisher J, Borysiewicz LK. Subsets of CD8+, CD57+ cells in normal, healthy individuals: correlations with human cytomegalovirus (HCMV) carrier status, phenotypic and functional analyses. Clin Exp Immunol. 1993;94:297–305. doi: 10.1111/j.1365-2249.1993.tb03447.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b93] 93.Tarazona R, Casado JG, Soto R, DelaRosa O, Peralbo E, Rioja L, Peña J, Solana R. Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword? Cancer Immunol Immunother. 2004;53:911–24. doi: 10.1007/s00262-004-0507-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b94] 94.Henel G, Singh K, Cui D, Pryshchep S, Lee WW, Weyand CM, Goronzy JJ. Uncoupling of T-cell effector functions by inhibitory killer immunoglobulin-like receptors. Blood. 2006;107:4449–57. doi: 10.1182/blood-2005-06-2519. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b95] 95.Vivier E, Anfossi N. Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future. J Immunol. 2006;176:6121–9. doi: 10.1038/nri1306. [DOI] [PubMed] [Google Scholar]

[b96] 96.Tarazona R, DelaRosa O, Alonso C, Ostos B, Espejo J, Peña J, Solana R. Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech Ageing Dev. 2000;121:77–88. doi: 10.1016/s0047-6374(00)00199-8. [DOI] [PubMed] [Google Scholar]

[b97] 97.Warren HS, Rana PM, Rieger DT, Hewitt KA, Dahlstrom JE, Kent AL. CD8 T cells expressing killer Ig-like receptors and NKG2A are present in cord blood and express a more naïve phenotype than their counterparts in adult blood. J Leukoc Biol. 2006;79:1252–9. doi: 10.1189/jlb.0905536. [DOI] [PubMed] [Google Scholar]

[b98] 98.Figueiredo C, Seltsam A, Blasczyk R. Permanent silencing of NKG2A expression for cell-based therapeutics. J Mol Med. 2009;87:199–210. doi: 10.1007/s00109-008-0417-0. [DOI] [PubMed] [Google Scholar]

[b99] 99.Natarajan K, Dimasi N, Wang J, Mariuzza RA, Margulies DH. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol. 2002;20:853–85. doi: 10.1146/annurev.immunol.20.100301.064812. [DOI] [PubMed] [Google Scholar]

[b100] 100.Ibegbu CC, Xu YX, Harris W, Maggio D, Miller JD, Kourtis AP. Expression of killer cell lectin-like receptor G1 on antigen-specific human CD8+ T lymphocytes during active, latent, and resolved infection and its relation with CD57. J Immunol. 2005;174:6088–94. doi: 10.4049/jimmunol.174.10.6088. [DOI] [PubMed] [Google Scholar]

[b101] 101.Simpson RJ. Aging, persistent viral infections, and immunosenescence: can exercise “make space”? Exerc Sport Sci Rev. 2011;39:23–33. doi: 10.1097/JES.0b013e318201f39d. [DOI] [PubMed] [Google Scholar]

[b102] 102.Blackburn SD, Crawford A, Shin H, Polley A, Freeman GJ, Wherry EJ. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J Virol. 2010;84:2078–89. doi: 10.1128/JVI.01579-09. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b103] 103.Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–45. doi: 10.1038/ni1443. [DOI] [PubMed] [Google Scholar]

[b104] 104.Khaitan A, Unutmaz D. Revisiting immune exhaustion during HIV infection. Curr HIV/AIDS Rep. 2011;8:4–11. doi: 10.1007/s11904-010-0066-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b105] 105.Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634–43. doi: 10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]

[b106] 106.Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8. doi: 10.1038/85330. [DOI] [PubMed] [Google Scholar]

[b107] 107.Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, Sharpe AH. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol. 2003;33:2706–16. doi: 10.1002/eji.200324228. [DOI] [PubMed] [Google Scholar]

[b108] 108.Sauce D, Almeida JR, Larsen M, Haro L, Autran B, Freeman GJ, Appay V. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS. 2007;21:2005–13. doi: 10.1097/QAD.0b013e3282eee548. [DOI] [PubMed] [Google Scholar]

[b109] 109.Effros RB, Boucher N, Porter V, et al. Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol. 1994;29:601–9. doi: 10.1016/0531-5565(94)90073-6. [DOI] [PubMed] [Google Scholar]

[b110] 110.Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schächter F. CD28 expression in T cell aging and human longevity. Exp Gerontol. 1998;33:267–82. doi: 10.1016/s0531-5565(97)00132-0. [DOI] [PubMed] [Google Scholar]

[b111] 111.Looney RJ, Falsey A, Campbell D, et al. Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol. 1999;90:213–9. doi: 10.1006/clim.1998.4638. [DOI] [PubMed] [Google Scholar]

[b112] 112.Fagnoni FF, Vescovini R, Mazzola M, et al. Expansion of cytotoxic CD8++ CCD28− T cells in healthy ageing people, including centenarians. Immunology. 1996;88:501–7. doi: 10.1046/j.1365-2567.1996.d01-689.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b113] 113.Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O'Fallon WM, Weyand CM. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol. 2001;75:12182–7. doi: 10.1128/JVI.75.24.12182-12187.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b114] 114.Saurwein-Teissl M, Lung TL, Marx F, et al. Lack of antibody production following immunization in old age: association with CD8+ CD28− T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol. 2002;168:5893–9. doi: 10.4049/jimmunol.168.11.5893. [DOI] [PubMed] [Google Scholar]

[b115] 115.Trzonkowski P, Myśliwska J, Szmit E, Wieckiewicz J, Lukaszuk K, Brydak LB, Machała M, Myśliwski A. Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination – an impact of immunosenescence. Vaccine. 2003;21:3826–36. doi: 10.1016/s0264-410x(03)00309-8. [DOI] [PubMed] [Google Scholar]

[b116] 116.Focosi D, Petrini M. CD57 expression on lymphoma microenvironment as a new prognostic marker related to immune dysfunction. J Clin Oncol. 2007;25:1289–91. doi: 10.1200/JCO.2006.10.2251. [DOI] [PubMed] [Google Scholar]

[b117] 117.Wikby A, Ferguson F, Forsey R, et al. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci. 2005;60:556–65. doi: 10.1093/gerona/60.5.556. [DOI] [PubMed] [Google Scholar]

[b118] 118.Simpson RJ, Cosgrove C, Chee MM, et al. Senescent phenotypes and telomere lengths of peripheral blood T-cells mobilized by acute exercise in humans. Exerc Immunol Rev. 2010;16:40–55. [PubMed] [Google Scholar]

[b119] 119.Turner JE, Aldred S, Witard OC, Drayson MT, Moss PM, Bosch JA. Latent cytomegalovirus infection amplifies CD8 T-lymphocyte mobilisation and egress in response to exercise. Brain Behav Immun. 2010;24:1362–70. doi: 10.1016/j.bbi.2010.07.239. [DOI] [PubMed] [Google Scholar]

[b120] 120.Meloni F, Morosini M, Solari N, et al. Foxp3 expressing CD4+ CD25+ and CD8+ CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum Immunol. 2006;67:1–12. doi: 10.1016/j.humimm.2005.11.005. [DOI] [PubMed] [Google Scholar]

[b121] 121.Characiejus D, Pasukoniene V, Jonusauskaite R, Azlauskaite N, Aleknavicius E, Mauricas M, Otter WD. Peripheral blood CD8high CD57+ lymphocyte levels may predict outcome in melanoma patients treated with adjuvant interferon-alpha. Anticancer Res. 2008;28:1139–42. [PubMed] [Google Scholar]

[b122] 122.Characiejus D, Pasukoniene V, Kazlauskaite N, Valuckas KP, Petraitis T, Mauricas M, Den Otter W. Predictive value of CD8high CD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. Anticancer Res. 2002;22:3679–83. [PubMed] [Google Scholar]

[b123] 123.Characiejus D, Pasukoniene V, Jacobs JJ, et al. Prognostic significance of peripheral blood CD8high CD57+ lymphocytes in bladder carcinoma patients after intravesical IL-2. Anticancer Res. 2011;31:699–703. [PubMed] [Google Scholar]

[b124] 124.Okada T, Iiai T, Kawachi Y, Moroda T, Takii Y, Hatakeyama K, Abo T. Origin of CD57+ T cells which increase at tumour sites in patients with colorectal cancer. Clin Exp Immunol. 1995;102:159–66. doi: 10.1111/j.1365-2249.1995.tb06650.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b125] 125.Serrano D, Monteiro J, Allen SL, et al. Clonal expansion within the CD4+ CD57+ and CD8+ CD57+ T cell subsets in chronic lymphocytic leukemia. J Immunol. 1997;158:1482–9. [PubMed] [Google Scholar]

[b126] 126.Vidriales MB, Orfao A, López-Berges MC, et al. Lymphoid subsets in acute myeloid leukemias: increased number of cells with NK phenotype and normal T-cell distribution. Ann Hematol. 1993;67:217–22. doi: 10.1007/BF01715050. [DOI] [PubMed] [Google Scholar]

[b127] 127.Kook H, Zeng W, Guibin C, Kirby M, Young NS, Maciejewski JP. Increased cytotoxic T cells with effector phenotype in aplastic anemia and myelodysplasia. Exp Hematol. 2001;29:1270–7. doi: 10.1016/s0301-472x(01)00736-6. [DOI] [PubMed] [Google Scholar]

[b128] 128.Dondi E, Roué G, Yuste VJ, Susin SA, Pellegrini S. A dual role of IFN-alpha in the balance between proliferation and death of human CD4+ T lymphocytes during primary response. J Immunol. 2004;173:3740–7. doi: 10.4049/jimmunol.173.6.3740. [DOI] [PubMed] [Google Scholar]

[b129] 129.Characiejus D, Hodzic J, Jacobs JJ. “First do no harm” and the importance of prediction in oncology. EPMA J. 2010;1:369–75. doi: 10.1007/s13167-010-0042-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b130] 130.Labalette M, Salez F, Pruvot FR, Noel C, Dessaint JP. CD8 lymphocytosis in primary cytomegalovirus (CMV) infection of allograft recipients: expansion of an uncommon CD8+ CD57− subset and its progressive replacement by CD8+ CD57+ T cells. Clin Exp Immunol. 1994;95:465–71. doi: 10.1111/j.1365-2249.1994.tb07020.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b131] 131.Wallace DL, Masters JE, De Lara CM, et al. Human cytomegalovirus-specific CD8+ T-cell expansions contain long-lived cells that retain functional capacity in both young and elderly subjects. Immunology. 2011;132:27–38. doi: 10.1111/j.1365-2567.2010.03334.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b132] 132.Petrova M, Muhtarova M, Nikolova M, Magaev S, Taskov H, Nikolovska D, Krastev Z. Chronic Epstein–Barr virus-related hepatitis in immunocompetent patients. World J Gastroenterol. 2006;12:5711–6. doi: 10.3748/wjg.v12.i35.5711. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b133] 133.Manfras BJ, Weidenbach H, Beckh KH, Kern P, Möller P, Adler G, Mertens T, Boehm BO. Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy. J Clin Immunol. 2004;24:258–71. doi: 10.1023/B:JOCI.0000025447.23473.ab. [DOI] [PubMed] [Google Scholar]

[b134] 134.Isa A, Kasprowicz V, Norbeck O, et al. Prolonged activation of virus-specific CD8+ T cells after acute B19 infection. PLoS Med. 2005;2:e343. doi: 10.1371/journal.pmed.0020343. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b135] 135.Aronsson B, Troye-Blomberg M, Smedman L. Increase of circulating CD8+ CD57+ lymphocytes after measles infection but not after measles vaccination. J Clin Lab Immunol. 2004;53:1–12. –2005. [PubMed] [Google Scholar]

[b136] 136.Kaplan RC, Sinclair E, Landay AL, et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis. 2011;203:452–63. doi: 10.1093/infdis/jiq071. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b137] 137.Cao W, Jamieson BD, Hultin LE, Hultin PM, Effros RB, Detels R. Premature aging of T cells is associated with faster HIV-1 disease progression. J Acquir Immune Defic Syndr. 2009;50:137–47. doi: 10.1097/QAI.0b013e3181926c28. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b138] 138.Scheinberg P, Melenhorst JJ, Brenchley JM, et al. The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. Blood. 2009;114:5071–80. doi: 10.1182/blood-2009-04-214684. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b139] 139.Bernal-Fernandez G, Espinosa-Cueto P, Leyva-Meza R, Mancilla N, Mancilla R. Decreased expression of T-cell costimulatory molecule CD28 on CD4 and CD8 T cells of Mexican patients with pulmonary tuberculosis. Tuberculosis Research and Treatment. 2010;2010:517547. doi: 10.1155/2010/517547. DOI: 10.1155/2010/517547. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b140] 140.Stricker RB, Burrascano J, Winger E. Longterm decrease in the CD57 lymphocyte subset in a patient with chronic Lyme disease. Ann Agric Environ Med. 2002;9:111–3. [PubMed] [Google Scholar]

[b141] 141.Wang EC, Lawson TM, Vedhara K, Moss PA, Lehner PJ, Borysiewicz LK. CD8high+CD57+ T cells in patients with rheumatoid arthritis. Arthritis Rheum. 1997;40:237–48. doi: 10.1002/art.1780400208. [DOI] [PubMed] [Google Scholar]

[b142] 142.Fasth AE, Dastmalchi M, Rahbar A, et al. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. J Immunol. 2009;183:4792–9. doi: 10.4049/jimmunol.0803688. [DOI] [PubMed] [Google Scholar]

[b143] 143.Scarsi M, Ziglioli T, Airò P. Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response. J Rheumatol. 2010;37:911–6. doi: 10.3899/jrheum.091176. [DOI] [PubMed] [Google Scholar]

[b144] 144.Klaus G, Mostert K, Reckzeh B, Mueller TF. Phenotypic changes in lymphocyte subpopulations in pediatric renal-transplant patients after T-cell depletion. Transplantation. 2003;76:1719–24. doi: 10.1097/01.TP.0000100396.81490.0C. [DOI] [PubMed] [Google Scholar]

[b145] 145.Vlad G, Cortesini R, Suciu-Foca N. CD8+ T suppressor cells and the ILT3 master switch. Hum Immunol. 2008;69:681–6. doi: 10.1016/j.humimm.2008.08.286. [DOI] [PubMed] [Google Scholar]

[b146] 146.Suciu-Foca N, Cortesini R. Central role of ILT3 in the T suppressor cell cascade. Cell Immunol. 2007;248:59–67. doi: 10.1016/j.cellimm.2007.01.013. [DOI] [PubMed] [Google Scholar]

[b147] 147.Song K, Coleman RA, Alber C, Ballas ZK, Waldschmidt TJ, Mortari F, LaBrecque DR, Cook RT. TH1 cytokine response of CD57+ T-cell subsets in healthy controls and patients with alcoholic liver disease. Alcohol. 2001;24:155–67. doi: 10.1016/s0741-8329(01)00146-x. [DOI] [PubMed] [Google Scholar]

[b148] 148.Olloquequi J, Montes JF, Prats A, Rodríguez E, Montero MA, García-Valero J, Ferrer J. Significant increase of CD57+ cells in pulmonary lymphoid follicles of COPD patients. Eur Respir J. 2011;37:289–98. doi: 10.1183/09031936.00201509. [DOI] [PubMed] [Google Scholar]

[b149] 149.Sharma G, Hanania NA, Shim YM. The aging immune system and its relationship to the development of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6:573–80. doi: 10.1513/pats.200904-022RM. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

CD8⁺ CD28⁻ and CD8⁺ CD57⁺ T cells and their role in health and disease

Marius Strioga

Vita Pasukoniene

Dainius Characiejus

Abstract

Introduction

Features of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Proliferative capacity CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Dilemma of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell senescence

Apoptotic potential of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Figure 1.

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell subsets

Cytotoxic CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell subsets

Immunosuppressive CD8⁺ CD28⁻ and CD8⁺ CD57⁺ T-cell subsets

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁺ T-cell subset

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁻ T-cell subset

Immunosuppressive CD8⁺ CD57⁺ T-cell subset

Expression of natural killer cell receptors on CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Late-differentiated CD28⁻ (CD57⁺) T cells versus PD-1-positive exhausted T cells

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells in health and disease

Ageing

High-intensity physical activity

Cancer

Chronic viral infections

Non-viral infections

Autoimmune diseases

Transplantation

Chronic alcoholism

Chronic pulmonary diseases

Glossary

Abbreviations

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease

Marius Strioga

Vita Pasukoniene

Dainius Characiejus

Abstract

Introduction

Features of CD8+ CD28− (CD8+ CD57+) T cells

Proliferative capacity CD8+ CD28− (CD8+ CD57+) T cells

Dilemma of CD8+ CD28− (CD8+ CD57+) T-cell senescence

Apoptotic potential of CD8+ CD28− (CD8+ CD57+) T cells

Figure 1.

CD8+ CD28− (CD8+ CD57+) T-cell subsets

Cytotoxic CD8+ CD28− (CD8+ CD57+) T-cell subsets

Immunosuppressive CD8+ CD28− and CD8+ CD57+ T-cell subsets

Immunosuppressive CD8+ CD28− FOXP3+ T-cell subset

Immunosuppressive CD8+ CD28− FOXP3− T-cell subset

Immunosuppressive CD8+ CD57+ T-cell subset

Expression of natural killer cell receptors on CD8+ CD28− (CD8+ CD57+) T cells

Late-differentiated CD28− (CD57+) T cells versus PD-1-positive exhausted T cells

CD8+ CD28− (CD8+ CD57+) T cells in health and disease

Ageing

High-intensity physical activity

Cancer

Chronic viral infections

Non-viral infections

Autoimmune diseases

Transplantation

Chronic alcoholism

Chronic pulmonary diseases

Glossary

Abbreviations

References

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

CD8⁺ CD28⁻ and CD8⁺ CD57⁺ T cells and their role in health and disease

Features of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Proliferative capacity CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Dilemma of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell senescence

Apoptotic potential of CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell subsets

Cytotoxic CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T-cell subsets

Immunosuppressive CD8⁺ CD28⁻ and CD8⁺ CD57⁺ T-cell subsets

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁺ T-cell subset

Immunosuppressive CD8⁺ CD28⁻ FOXP3⁻ T-cell subset

Immunosuppressive CD8⁺ CD57⁺ T-cell subset

Expression of natural killer cell receptors on CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells

Late-differentiated CD28⁻ (CD57⁺) T cells versus PD-1-positive exhausted T cells

CD8⁺ CD28⁻ (CD8⁺ CD57⁺) T cells in health and disease