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. 2005 Apr;114(4):493–498. doi: 10.1111/j.1365-2567.2004.02113.x

Complement receptors regulate lipopolysaccharide-induced T-cell stimulation

Ziya Kaya 1,2, Theresa Tretter 3, Jens Schlichting 2, Florian Leuschner 1,2, Marina Afanasyeva 2, Hugo A Katus 1, Noel R Rose 2
PMCID: PMC1782106  PMID: 15804286

Abstract

Complement receptors type 1 and 2 (CR1 (CD35)/CR2 (CD21)) are known to enhance the adaptive immune response. In mice, CR1/CR2 are expressed on B cells, follicular dendritic cells, and activated granulocytes. Recently, we showed that a subset of CD44high and CD62Llow T cells also expresses CR1 and CR2. We now report that CR1/CR2 are detectable on both CD4+ and CD8+ subsets of T cells. Lipopolysaccharide (LPS) from Gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other antigen-presenting cells. We further demonstrate that LPS induced marked up-regulation of CD25 and CD69 on T cells from CR1/CR2 sufficient (Cr+/+), but significantly lower up-regulation on T cells from CR1/CR2 deficient (Cr–/–) mice. These findings point to a novel mechanism by which CR1/CR2 modulates the activation of T cells by LPS.

Keywords: T lymphocytes, lipopolysaccharide, complement, cell surface molecules, cellular activation

Introduction

In mice, complement receptors type 1 (CR1 or CD35) and type 2 (CR2 or CD21) are encoded at a single locus (Cr2) on chromosome 1 and are predominantly expressed on B cells, follicular dendritic cells, and activated granulocytes.1 Recently, we showed that also a subset of CD44high and CD62Llow T cells also expresses CR1/CR2.2 Later studies suggested an important role for CR1/CR2 in the initiation and regulation of the adaptive immune response through antigen trapping, B-cell activation, and immunoglobulin class switching.3–5 Furthermore, the CR2, also known as a receptor for Epstein–Barr virus and complement component C3d, has been identified as the major interferon-α (IFN-α) receptor on B cells.6 Even though these receptors have been described on human thymocytes and a subset of peripheral blood T cells7–9 their function is not known.

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is well known for its capacity to cause polyclonal activation of B cells. In addition, LPS is strongly stimulatory for macrophages and other antigen-presenting cells (APC), inducing these cells to release various cytokines, such as type I (α, β) interferon (IFN-I), tumour necrosis factor-α (TNF-α), and interleukin (IL)-12.10,11 A few studies indicate that LPS can also stimulate T cells.12–15 Hence, LPS can act as a powerful adjuvant for T-cell responses to a specific antigen12,13 and for the induction of autoimmune disease even in genetically resistant mice.16 LPS may also stimulate certain T-cell clones and a small proportion (1–3%) of splenic T cells in vitro.14 Recently, it has been shown that T cells can also be activated by administration of LPS in vivo.15 Based on studies with LPS-non-responder and gene-knockout mice, the authors concluded that LPS-induced stimulation and proliferation of T cells operate via an indirect pathway involving LPS stimulation of APC and release of IFN-I.15 However, the mechanism by which LPS stimulates T cells is not yet known.

To assess the possibility that complement receptors are involved in LPS-induced T-cell stimulation, we further screened T cells for the expression of CR1/CR2 and examined the role of complement receptors in LPS-mediated T-cell stimulation using Cr+/+ and Cr–/– mice.

Materials and methods

Mice

Cr–/– mice (C57BL/6) were generously provided by Dr V. Michael Holers (University of Colorado Health Science Center, Denver, CO), then back-crossed five generations onto the A/J background. The Cr+/– mice were then interbred to get Cr+/+ and Cr–/– mice on the same genetic background. Age-matched male Cr+/+ or Cr–/– A/J mice were used in all experiments. Mice were maintained in the conventional animal facility at Johns Hopkins School of Medicine.

Immunization of the mice and cell culture

In replicate experiments groups of five to seven Cr–/– and five to seven Cr+/+ mice were either immunized subcutaneously with 50 µg of hen egg lysozyme (HEL, Sigma, St. Louis, MO) in complete Freund's adjuvant (CFA; Sigma) on days 0 and 7 and killed on day 10 or were not immunized. The spleen of each mouse was teased into single cell suspensions in RPMI-1640 (Life Technologies, Grand Island, NY). The splenic cells were sedimented and washed twice with 15 ml of fresh RPMI-1640 by centrifugation at 330 g for 8 min. The viable cells were counted by trypan blue exclusion, and suspended at 106 cells/ml in RPMI-1640 medium which was supplemented with 10% fetal calf serum, 15 mm HEPES, 1%l-glutamine, 1% minimal essential medium vitamins, 1% non-essential amino acid, 0·1 mmβ-mercaptoethanol, 1% sodium pyruvate and 100 U/ml of penicillin–streptomycin (Life Technologies). Cells were either used for isolation of B cells and T cells or were cultured in the presence of LPS (1 µg/ml, 10 µg/ml, 25 µg/ml, or 100 µg/ml, LPS from Escherichia coli 055:B5, Sigma) or medium alone for 24 or 48 hr followed by fluorescence-activated cell sorting (FACS) analysis.

Blocking of CR1/CR2 with mAb 7G6

Groups of four Cr+/+ mice were immunized subcutaneously with 50 µg of hen egg lysozyme (HEL; Sigma) in CFA (Sigma) on days 0 and 7 and killed on day 10. The splenic cells were isolated as described above. Cells were cultured in the presence of LPS (10 µg/ml, 25 µg/ml, or 100 µg/ml, LPS from E. coli 055:B5, Sigma) for 24 or 48 hr followed by either no cotreatment (medium alone) or cotreatment with 100 µg/ml 7G6 monoclonal antibody (mAb, to block CR1/CR2)2 or cotreatment with 100 µg/ml isotype-matched control mAb (rat immunoglobulin G2b (IgG2b) from clone A95-1)2 and by FACS analysis.

Isolation of B cells, T cells, and macrophages

In replicate experiments groups of five to seven Cr–/– and five to seven Cr+/+ mice were immunized as described above and killed on day 10. Spleens and lymph nodes were collected. B cells were purified using B220 micro beads (Miltenyi Biotec, Auburn, CA) according to the manufacturer's instructions. T cells were purified from the eluate using T-cell enrichment columns (R & D Systems, Minneapolis, MN). Peritoneal macrophages were isolated by their ability to adhere to culture plates. Purity was over 95% as assessed by FACS analysis. Cells were cultured in different combinations (Cr+/+ or Cr–/– B cells with Cr+/+ or Cr–/– T cells, Cr+/+ or Cr–/–macrophages with Cr+/+ or Cr–/– T cells) with different concentrations of LPS (1 µg/ml, 10 µg/ml, 25 µg/ml, or 100 µg/ml) or medium alone for 24 or 48 hr followed by FACS analysis.

FACS analysis

Spleen-cells were collected, counted (5 × 105 cells per FACS tube), washed, and resuspended in phosphate-buffered saline (containing 1% fetal calf serum and 0·01% sodium azide). Fc receptors were blocked with anti-CD16/32 (clone 2.4G2). Cells were then washed and stained directly with cytochrome-, fluorescein isothiocyanate (FITC)- or phycoerythrin (PE)-conjugated anti-CD3, anti-CD4, anti-CD8, anti-CD21/35, anti-CD25, anti-CD44, anti-CD62L, and anti-CD69 (all antibodies were purchased from Pharmingen, San Diego, CA). Cytochrome-, FITC- or PE-conjugated isotype-matched antibodies were used as controls. After staining cells were fixed with 1% paraformaldehyde. Fluorescence signals were determined using a FACScan (Becton Dickinson, San Jose, CA).

Results

A subset of CD4+ and CD8+ T cells expresses CR1/CR2

We have recently shown that a subset of CD44high and CD62Llow T cells but not naive, CD44low and CD62Lhigh T cells expresses CR1/CR2. To further characterize this finding we stained splenocytes from Cr+/+ mice immunized with HEL with anti-CD3, anti-CD4, and anti-CD8 anti-CR1/CR2. CR1/CR2 were detected on a proportion of both CD4+ (24 ± 6%) and CD8+ subsets of T cells (13 ± 4%; Fig. 1).

Figure 1.

Figure 1

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Expression of CR1/CR2 on a subset of CD4+ and CD8+ T cells. Triple staining of splenocytes from Cr+/+ mice was performed using PE-labelled anti-CD3, FITC-labelled anti-CR1/CR2, and cytochrome-labelled anti-CD4 or anti-CD8. Numbers present the percentage of CD3+, CD4+ or CD8+ cells staining with the indicated marker Density plot.

LPS-induced expression of CD69 and CD25 on T cells

Spleens from non-immunized and immunized Cr+/+ and Cr–/– mice were collected and splenocytes were isolated, washed and cultured in the presence of LPS or anti-CD3 for 24 hr followed by FACS analysis for the expression of activation markers CD69 and CD25 on T cells. When stimulated with LPS T cells from immunized Cr+/+ mice expressed significantly more CD69 on their surface than T cells from Cr–/– mice (56% ± 12 versus 29% ± 14; Fig. 2). Yet when stimulated by plate-bound, cross-linked anti-CD3 T cells from Cr–/– mice had the same level of CD69 expression on their cell surface as the T cells from Cr+/+ mice. Upon LPS stimulation non-T cells (CD3– cells) from Cr+/+ and Cr–/– mice were activated to comparable levels (44 ± 9% versus 39 ± 8%). In non-immunized mice LPS-induced T-cell expression of CD69 or CD25 was very low at all LPS concentrations tested (1 µg/ml, 10 µg/ml, and 25 µg/ml) in both Cr+/+ and Cr–/– mice and no significant differences were seen between the expression of CD69 or CD25 on Cr+/+ and Cr–/– T cells (data not shown).

Figure 2.

Figure 2

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Expression of CD69 on Cr+/+ or CR–/– T cells. Splenocytes from immunized Cr+/+ and Cr–/– mice were cultured in the presence of 25 µg/ml LPS, plate-bound anti-CD3 antibodies, or medium alone for 24 hr followed by FACScan analysis for the expression of CD69 on T cells. Numbers present the percentage of CD3+ cells staining with the indicated marker Dotplot. *P < 0·05.

Blocking CR1/CR2 by mAb (7G6) also reduced significantly the expression of CD25 and CD69 on CD3+(Fig. 3), CD4+, and CD8+ (data not shown) T cells in LPS immunized mice independent of the LPS concentration used for in vitro stimulation of the splenocytes (10 µg/ml, 25 µg/ml, or 100 µg/ml).

Figure 3.

Figure 3

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Expression of CD25 and CD69 on CD3+ T cells. Splenocytes from immunized wild type mice were cultured in the presence of 10 µg/ml, 25 µg/ml or 100 µg/ml LPS or no antibody (medium), 100 µg/ml control antibody or 100 µg/ml 7G6 mAb for 24 hr followed by FACScan analysis for the expression of CD25 and CD69 on T cells. Numbers present the percentage of CD3+ cells staining with the indicated marker. *P < 0·05.

To delineate the role of CR1/CR2 in the LPS-induced activation of T cells, we separated T cells, B cells, and macrophages from immunized Cr+/+ and Cr–/– mice using magnetic beads and cell enrichment columns. The T cells from Cr+/+ or Cr–/– mice were then cultured in the presence of either B cells or macrophages from Cr+/+ or Cr–/– mice. After stimulation with 25 µg/ml LPS for 24 hr, cells were assessed by FACS analysis for the expression of the early activation markers CD25 and CD69. T cells from Cr+/+ mice cultured with macrophages had higher expression of CD25 (24·5 ± 4%/21·5 ± 3% versus 14·5 ± 3%/12 ± 2%) and CD69 (41·5 ± 7%/50·5 ± 8% versus 19 ± 2%/21·5 ± 4%) than T cells from Cr–/– mice. The higher expression of these activation markers was not dependent upon whether the macrophages came from Cr+/+ or Cr–/– donors (Fig. 4). The differential effect of LPS was not observed when T cells were cultured in presence of purified B cells as APC (data not shown).

Figure 4.

Figure 4

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Expression of CD69 and CD25 on T cells in culture with macrophages. Numbers present the percentage of CD3+ cells staining with the indicated marker; T, T cells; Mac, macrophages. *P < 0·05.

Discussion

We have recently shown that in mice a subset of activated, CD44high and CD62Llow T cells expresses CR1/CR2. This expression was not seen on naive, CD44low and CD62Lhigh T cells.2 The results presented here demonstrate that both CD4+ and CD8+ subsets of T cells express CR1/CR2 in mice. Our finding suggests that these complement receptors play a critical role in LPS-induced T-cell stimulation. After LPS stimulation in vitro, Cr+/+ T cells from immunized mice showed a remarkably higher expression of early activation markers, such as CD69 and CD25, than Cr–/– T cells. This markedly enhanced expression of CD69 and CD25 on T cells was not observed in cells from non-immunized mice. Based on studies with separated B cells, macrophages and T cells, LPS-induced T-cell activation, as manifested by CD69 and CD25 up-regulation, appears to operate via an indirect pathway involving LPS stimulation of APCs and release of certain cytokines. By antibody dependent blockade of IFN-I, the differences observed in CD69 and CD25 expression on Cr+/+ and Cr–/– T cells were partially reduced (unpublished observation). Overall, our data indicate that LPS-induced stimulation of T cells requires both the expression of CR1/CR2 on T cells and the presence of macrophages. The effects are mediated in part by IFN-I produced by the macrophages.15

The expression of CR1/CR2 on both CD4+ and CD8+ subsets of T cells in mice is a novel finding and provides additional insight into the mechanism of the transition from innate to adaptive immune responses. Even though in few studies these receptors have been described7–9,17 their exact function is unknown. B cells and follicular dendritic cells are known to express CR1/CR21 and many groups have studied the function of these receptors on these cells. The role of CR1/CR2 in antigen-trapping, formation of germinal centres, B-cell maturation, and long-term memory B-cell development have been described.3–5 Lately, it has been reported that B cells of human immunodeficiency virus (HIV)-1-infected patients bind virions through CR2–complement interaction and transmit infectious virus to activated T cells.18 After transition from the acute to the chronic phase of HIV infection, complement mediates long-term storage of virions in germinal centres of lymphoid tissue through CR1/CR2 on follicular dendritic cells.19 The finding that CR1/CR2 is mostly expressed on a subset of activated T cells may explain why HIV predominantly infects activated T cells.

Recently, it has been reported that T cells can be activated by administration of LPS in vivo.15 Our in vitro findings confirm these in vivo results. Furthermore, we can now propose a likely mechanism to explain how LPS might activate T cells. Based on our findings we suggest that LPS stimulation leads to release of cytokines produced by APCs (macrophages), which then stimulate a subset of T cells. One cytokine that might act on CR1/CR2 is IFN-α, since we could consistently reduce the expression of CD69 and CD25 on Cr+/+ T cells by blocking with anti-IFN-I (unpublished observation). This hypothesis is supported by the findings of Delcayre et al. showing that IFN-α contains a sequence motif similar to the CR2 binding site on complement fragment C3d. Therefore they concluded that CR2 or CR2-like molecules might be the major IFN-α receptors on B cells.8 Other studies support the potential of IFN-I to stimulate T cells.20,21 Because blocking IFN-I only partly decreased the up-regulation of the activation markers and only incompletely reduced the differences observed in the activation of Cr+/+ and Cr–/– T cells (unpublished observation), we conclude that additional cytokines produced by APCs are involved in LPS-induced T-cell activation. These products may act in synergy with IFN-I. Blocking the biological activity of IL-12 by a neutralizing anti-IL-12 mAb has been demonstrated to reduce T-cell activation. However, IL-12 alone is not able to induce proliferation in resting T lymphocytes, but only stimulates activated T cells or T-cell clones.22 Separating macrophages from T cells by a semipermeable membrane preventing direct cell-to-cell contact abrogated their capacity to induce T-cell stimulation, implying that additional direct cell-to-cell contact between macrophages and T cells is required for T-cell activation.23,23,24 We can not exclude the possibility that the expression of CR1/CR2 on B cells and follicular dendritic cells (FDC) may also have an important role in priming T cells because we do not see significant differences in non-immunized mice and the absence of CR1/CR2 on B cells and FDC leads to defects in mounting immune responses.

To summarize we previously reported that a subset of CD44high and CD62Llow T cells expresses CR1 and CR2.2 Now we demonstrate that CR1/CR2 can be detected on both CD4+ and CD8+ subsets of T cells in mice and that these receptors play a critical role in LPS-induced T-cell stimulation. These novel findings bring new insight to understanding the adjuvant effect of LPS.

Acknowledgments

The authors thank V. Michael Holers (University of Colorado Health Science Center, Denver, CO) for providing the Cr–/– mice, Saied Mirshahidi and Özay Kaya for critically reading the manuscript and Renate Öttl for technical assistance. The research was supported in part by the Deutsche Herzstiftung, by the Deutsche Forschungsgemeinschaft and by the National Institutes of Health grants HL70729, HL67290 and AI51835.

Abbreviations

APC

antigen presenting cell

CR1

complement receptor type 1

CR2

complement receptor type 2

FDC

follicular dendritic cell

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