Early events in the induction of allergic contact dermatitis

Innate recognition of haptens

It has long been recognized that the presence of foreign antigen alone is insufficient to generate immune responses: activation of the innate immune system is also required. In the case of vaccines, this is accomplished by combining antigen with adjuvants. In most cases, adjuvants contain microbial products (for example, mycobacteria in complete Freund’s adjuvant) that engage families of receptors which have evolved to recognize specific components of microbial organisms, that is, pathogen-associated molecular patterns (PAMPs). Many of these receptors can also respond to endogenous ligands to sense cell damage or necrosis. Historically, research into the immunology of acute contact dermatitis and contact hypersensitivity has overlooked hapten-mediated activation of the innate immune system to focus on the role of cutaneous antigen-presenting cells (APCs), such as Langerhans cells and dermal DC, and conventional CD8⁺ and CD4⁺ T cells. The importance of hapten-mediated activation of innate immunity is highlighted by the clinical observation that the irritancy of chemicals (that is, the ability of these chemicals to cause grossly visible skin inflammation upon primary exposure) correlates with their ability to act as contact sensitizers and to induce acute contact dermatitis.

Haptens activate Toll-like receptors

Toll-like receptors (TLRs) are a family of receptors that recognize PAMPs expressed by bacteria, parasites, viruses and fungi. TLRs are evolutionarily conserved in vertebrates and recognize a wide variety of ligands, including lipids, lipoproteins, proteins and nucleic acids¹⁸. TLRs trigger specific biological responses. For instance, TLR4-mediated recognition of lipopolysaccharide (LPS), a cell wall component found in gram-negative bacteria, induces the secretion of type I interferons (IFNs) and other pro-inflammatory cytokines. In contrast, activation of a cell via other TLRs, such as heterodimers of TLR1–TLR2 and TLR2–TLR6 or TLR5 homodimers, induces the secretion of pro-inflammatory cytokines but not IFN production. These differences are explained by differences in the downstream signaling pathways engaged by different TLRs. Most TLRs, with the exception of TLR3 and TLR4, signal exclusively via the adapter MyD88, which activates the transcription factor nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) to induce the expression of pro-inflammatory cytokines, such as IL-1β¹⁸. TLR3 signals via TIR-domain-containing adaptor protein inducing IFNβ (TRIF) leading to activation of the transcription factors interferon-regulatory factor 3 (IRF3) and NF-κB and results in induction of type I IFN and inflammatory cytokines. TLR4 signals via both TRIF and MyD88 resulting in activation of both signalling pathways. In addition to PAMPs, TLRs also recognize damage associated molecular patterns (DAMPs), which are self molecules that can be released during necrotic cell death. PAMPs comprise a diverse set of proteins, nucleic acids, and glycosaminoglycans; examples include heat shock proteins, HMGB1, RNA, DNA, hyaluronan, and heparin sulfate¹⁹.

Recently, a crucial role for TLR2 and TLR4 has been described in contact hypersensitivity, an experimental model of allergic contact dermatitis (Box 1)²⁰. Although mice deficient in either TLR2 or TLR4 developed normal contact hypersensitivity responses, mice lacking both of these TLRs were not sensitized and failed to develop contact hypersensitivity in response to the haptens trinitrochlorobenzene (TNCB), oxazolone and fluorescein isothiocyanate (FITC). Interestingly, if the mice were unable to respond to IL-12 the absence of either TLR2 or TLR4 alone was sufficient to prevent the development of optimal contact hypersensitivity²⁰. These data suggest that there are two possible mechanisms of sensitization to contact allergens: an IL-12-dependent one, in which activation of TLR2 or TLR4 alone is sufficient for contact hypersensitivity to develop, and a IL-12-independent mechanism that requires activation of both TLR2 and TLR4.

Since TLR2 and TLR4 do not directly recognize haptens, a role for commensal skin bacteria was evaluated by performing sensitization experiments in germ-free mice. These studies showed that contact hypersensitivity to TNCB develops normally in the absence of the bacterial flora²⁰. Thus, TLR2 and TLR4 appear to recognize endogenous host-derived ligands that are present in the skin, rather than components of the commensal flora. One candidate is low molecular weight breakdown products of high molecular weight hyaluronic acid (Figure 1)²¹. Low molecular weight-hyaluronic acid derivatives activate DCs in vitro via TLR2 and TLR4^{22, 23}. In addition, reactive oxygen species that are produced in response to haptens can induce breakdown of hyaluronic acid²⁴. Importantly, blockade of hyaluronic acid function in germ-free mice significantly reduces sensitization to haptens²⁰, which confirms a role for degraded hyaluronic acid as an endogenous activator of TLR2 and TLR4-mediated signaling in contact hypersensitivity responses. This observation has therapeutic implications, in that blockade of the formation of DAMPs may represent a novel approach to prevent allergic contact dermatitis in a naïve host, or lessen allergic contact dermatitis in an allergic host.

Haptens activate innate immunity via NLR receptors

A second system of PAMP recognition involves the formation of an intracellular complex of proteins termed the inflammasome (Figure 1)²⁵. The inflammasome complex includes proteins of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) gene family that sense foreign PAMPs or endogenous ligands through an incompletely understood mechanism. Engagement of these receptors leads to signaling through the adaptor protein ASC (apoptosis associated speck-like protein containing a caspase recruitment domain) to activate pro-caspase 1, which cleaves pro-IL-1β and pro-IL-18 into active forms. Since one outcome of TLR signaling is increased expression of mRNA for IL-1β, the TLR and inflammasome systems can work coordinately to induce the release of pro-inflammatory cytokines (Table 1).

The importance of this system in responding to haptens is demonstrated by the reduced sensitization to TNCB and dinitrofluorobenzene (DNFB) that occurs in ASC^−/−, NALP3^−/−, and caspase1^−/− mice^26-28. At least in the case of TNCB and oxazalone, inflammasome activation also depends on the ATP receptor P2X ²⁹₇. This indicates that inflammasome activation occurs indirectly as a result of cell damage and release of ATP. Interestingly, dinitrothiocyanobenzene (DNTB) is a weak sensitizer that can induce tolerance to the structurally related hapten DNFB. DNTB does not induce inflammasome-mediated secretion of active IL-1β and IL-18³⁰. However, artificial inflammasome induction with sodium dodecyl sulfate (SDS) or co-administration of IL-1β converts DNTB into a sensitizing agent. In addition, administration of low, sub-threshold doses of many haptens including DNFB can induce a long-lasting tolerance³¹. Thus, inflammasome activation may be a feature common to all sensitizing haptens.

Other skin allergens engage PRRs

Although the above mechanisms appear to be broadly applicable to allergic contact dermatitis, there are very specific examples of how PRRs are activated by certain human skin allergens. Nickel is the most common cause of allergic contact dermatitis and is known to activate NF-kB and MAPK signaling. Recently, human TLR4 was shown to be the crucial receptor for nickel-induced pro-inflammatory gene expression³². Nickel allergies in humans appear to be an accident of nature. Binding of nickel, but not of the natural ligand LPS, to human TLR4 requires the presence of two non-conserved histidine residues in human TLR4, H456 and H458. These histidines are absent from mouse TLR4, which explains the mystery of why mice fail to develop contact hypersensitivity to nickel³².

House dust mites can exacerbate eczema in patients with atopic dermatitis, and are also a major source of aeroallergens for patients with allergic asthma and activate innate immunity through a unique and important mechanism³³. Concentrated in mite faecal pellets, the major group 2 allergens, Der p 2 and Der f 2, are highly allergenic; among defined dust mite antigens, they have the highest rates of skin test positivity in patients with atopic dermatitis, and can also result in exacerbations of eczema. Sequence homology places these allergens in the recently recognized MD2-related lipid-recognition domain family of proteins³⁴. Der p 2 also has functional homology, facilitating signaling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signaling in the absence of MD-2. This property provides it with natural adjuvant properties that are highly relevant for its potency as a common skin and respiratory track allergen.

Keratinocytes

Keratinocytes are a crucial cell type for the development of allergic contact dermatitis due to their numerical abundance in the epidermis and through their role in the formation of the anatomic barrier function of the skin. Although haptens can penetrate through intact skin, the importance of an intact skin barrier in limiting sensitivity to allergic contact dermatitis has long been hypothesized based on the observation that patients with certain disease states that impair barrier function (for example, leg ulcers and peri-anal dermatitis) have an increased risk of sensitization to topically applied medications and their vehicle components. Recently, direct evidence has been obtained through the discovery that many patients with atopic dermatitis (an inherited form of allergic chronic dermatitis) or allergic contact dermatitis to nickel harbor a defective form of the filaggrin gene^{35, 36}. Filaggrin helps aggregate cytoskeletal proteins that form the cornified cell envelope. In its absence, the barrier is defective as determined by increased loss of water through the epidermis. The importance of filaggrin has been confirmed in mice into which the mutations observed in atopic dermatitis patients were genetically introduced³⁷. Mice with defective filaggrindevelop exaggerated responses to percutaneous immunization with proteins and haptens that results in a reduced threshold for allergic dermatitis^37-39.

In addition to physically blocking penetration, keratinocytes also recognize haptens via the mechanisms discussed above to generate the innate responses that are required for contact hypersensitivity (Figure 3a). Keratinocytes express most TLRs, except TLR7 and TLR8, and this allows them to respond to TLR4-triggering haptens, such as DNFB and nickel⁴⁰. Inflammasome-mediated secretion of IL-1β and IL-18 occurs in response to certain haptens. In addition to IL-1β and IL-18, keratinocytes secrete a large number of other pro-inflammatory cytokines and chemokines (reviewed in ^{41, 42}). Of particular importance is TNFα which, along with IL-1β and IL-18, is required for hapten-induced DC maturation and migration from the skin to the local lymph node^43-45. TNFα may be partially redundant, though, as TNFα^−/− mice have only somewhat reduced CHS⁴⁶.

It has been recently appreciated that in addition to inducing DC migration, keratinocytes can modulate the T cell response through ‘conditioning’ of skin-resident DCs. Perhaps the best example of this is the conditioning effects of keratinocyte-derived thymic stromal lymphopoietin (TSLP) on DCs⁴⁷. TSLP activates DCs to induce naive T cell differentiation into T helper 2 (T_H2) cells, which promote allergic responses^{48, 49}. The expression of TSLP is induced by dibutylphthalate (DBP), a vehicle often used in conjunction with FITC to generate a T_H2-type contact hypersensitivity response. The importance of TSLP has been confirmed with the observation that mice deficient in the TSLP receptor develop reduced contact hypersensitivity responses to FITC–DBP⁵⁰. TSLP is also expressed by keratinocytes isolated from patients with atopic dermatitis and may be a key contributor to the disease⁴⁸. A second conditioning factor, the receptor activator of –NF-κB ligand (RANKL), is expressed by keratinocytes in response to inflammation. Overexpression of RANKL by keratinocytes increases the number of regulatory T (T_Reg) cells, most likely through effects on Langerhans cells that express RANK⁵¹. Interestingly, UV-light and vitamin D3, which both increase expression of RANKL by keratinocytes, suppress contact hypersensitivity responses in mice and allergic contact dermatitis in humans^52-54.

In addition to promoting T_Reg cell responses through RANKL expression, keratinocytes also participate in suppressing the response. For example, the anti-microbial peptide, cathelicidin, is secreted by keratinocytes and inhibits hyaluronan-induced cytokine release⁵⁵. Cathelicidin-deficient mice develop exaggerated contact hypersensitivity to DNFB. Activated keratinocytes express high levels of MHC class I and MHC class II but have only low levels of expression of the costimulatory molecule CD80 (also known as B7.1). Transgenic overexpression of CD80 on keratinocytes leads to exaggerated contact hypersensitivity, which suggests that the absence of CD80 on keratinocytes could inhibit or anergize effector T cells^{56, 57}. Keratinocytes are also a source of IL-10, an immunosuppressive cytokine that limits the extent of contact hypersensitivity⁵⁸.

Dendritic cells

The key event in allergic contact dermatitis is the priming of hapten-specific naïve CD4⁺ and CD8⁺ T cells, which then become activated, proliferate, and differentiate into effector T cell subsets. This occurs in the regional lymph node. Although haptens can drain to the lymph node via lymphatic flow this does not lead to a productive T cell response^{59, 60}. Instead, antigen presentation in the lymph node by migratory DCs is absolutely essential for the generation of responses to peripheral antigen^59-61,62.

In the skin at steady state, there are several populations of DCs. Langerhans cells are the only DC subtype in the epidermis. Langerhans cell precursors first populate the epidermis on embryonic day 18 and proliferate in situ to form a radio-resistant, self-renewing population that is unique among dendritic cells (DCs)^{63, 64}. Like all skin-resident DCs, Langerhans cells efficiently acquire antigen in the periphery and migrate to regional lymph nodes where they present antigen to naïve and memory T cells⁶⁵. Hapten also penetrates into the dermis and is acquired by dermal DCs⁶⁶. Langerin⁺ dermal DCs (also referred to as CD103⁺ dermal DCs) are a distinct DC subset and arise from bone marrow precursors in a FMS-related tyrosine kinase 3 (FLT3)-dependent manner^67-71. Although they represent only a small percentage of the total DC population in the dermis (~3%), Langerin⁺ dermal DCs are in a high state of flux and are continually replaced by new recruits from the blood^{68, 72}. Examination of subset ontogeny has clearly identified that Langerhans cells and Langerin⁺ dermal DCs are distinct DC subsets^{63, 71, 73, 74} The second major dermal population, Langerin⁻ dermal DCs (also referred to as classic dermal DCs), make up the bulk of dermal DCs (~80%) and are heterogeneous, with at least two subsets that can be distinguished based on the expression of CD11b⁷². In response to inflammation, GR1+ monocytes are recruited to the skin where they develop into DC^{75, 76}. The functional importance to CHS of this important DC subset is unclear.

Studies examining the specific contribution of steady-state DC subsets to the hapten-specific immune response have been made possible by the existence of several mouse strains that lack specific DC subsets (Table 2). HuLangerin-DTA mice express the active subunit of diphtheria toxin (DTA) specifically in Langerhans cells and this leads to a constitutive absence of epidermal Langerhans cells ⁷⁷. HuLangerin-DTR mice express the primate diphtheria toxin receptor (DTR) in Langerhans cells and this enables inducible and specific ablation of Langerhans cells after injection of diphtheria toxin⁷⁸. These mice develop enhanced contact hypersensitivity responses to various contact allergens, but not irritants such as benzalkonium chloride. Experiments in which Langerhans cells were depleted at different time points showed that Langerhans cells have suppressive functions during the priming phase but not during the effector phase of the contact hypersensitivity response^77-79. Contact hypersensitivity responses are also exaggerated in huLangerin-Cre MHC-II^flox and huLangerin-Cre IL-10^flox mice suggesting that Langerhans cells suppress contact hypersensitivity responses in an IL-10-dependent manner and require cognate interaction with CD4⁺ T cells (Figure 3b)^{79, 80}. In addition to inhibiting contact hypersensitivity responses, Langerhans cells have suppressive functions in other immune models, and have been shown to promote tolerance to minor-mismatched skin grafts, suppress the clearance of Leishmania infection and mediate UV-induced immunosuppression ^81-84.

Table 2.

Effects of genetic ablation of DC subsets on the development of contact hypersensitivity

Mouse strain	Effects on dermal DC subsets				Effect on intensity of contact hypersensitivity response
	Epidermal Langerhans cells	Dermal Langerin+ DCs	Dermal Langerin- DCs	CD8+ DCs
Constitutive systems
huLangerin-DTA77	absent	normal	normal	normal
huLangerin-Cre79x IL-10flox or huLangerin-Cre x I-Abflox	Functionally defective	normal	normal	normal
Batf3−/−73	normal	absent	normal	absent	normal
Inducible systems
muLangerin-DTR (diphtheria toxin administered day +1)85, 86, 91	absent	absent	normal	~25% of DCs present
muLangerin-DTR (diphtheria toxin administered day ++7/13)67, 91	absent	~20-50% of DCs present	normal	normal	normal
huLangerin-DTR (diphtheria toxin administered day +1)78	absent	normal	normal	normal

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As discussed above, Langerin is expressed in Langerhans cells and a subset of dermal DC. In mice that express DTA or DTR under control of the human Langerin promoter, dermal DCs are not deleted. This is presumably due to difference between the human and murine langerin promoters. In contrast, in muLangerin-DTR mice, diphtheria toxin injection ablates Langerhans cells, Langerin⁺ dermal DCs and also CD103⁺ DCs from many other peripheral tissues^{85, 86}. CD8⁺ DCs that reside in lymph nodes and spleen are also eliminated with reduced efficiency. Contact hypersensitivity is greatly diminished in these mice if diphtheria toxin is administered prior to priming, but not prior to elicitation^85-87. Langerhans cells repopulate the skin after diphtheria toxin-mediated ablation much more slowly than Langerin⁺ dermal DCs⁶⁷. Interestingly, contact hypersensitivity responses develop normally in muLangerin-DTR mice if priming is delayed until 7-13 days after diphtheria toxin administration, a time-point when Langerhans cells are absent but Langerin⁺ dermal DCs have partially returned. This suggests that Langerin⁺ dermal DCs, rather than Langerhans cells, promote the development of contact hypersensitivity ^{67, 88}. This is supported by the observation that contact hypersensitivity responses can be adoptively transferred with dermal DCs, but not with Langerhans cells, isolated from sensitized mice⁸⁹. However, by using the delayed contact hypersensitivity technique or muLangerin-DTR bone marrow chimeras to selectively ablate Langerhans cells or Langerin⁺ dermal DCs, other groups have found that Langerin⁺ dermal DCs and Langerhans cells are functionally redundant^{90, 91}. Thus, distinguishing the function of Langerhans cells from Langerin⁺ dermal DCs using muLangerin-DTR mice is complicated by the complex experimental manipulations that are required to deplete individual DC subsets. However, in Batf3^−/− mice, which have a constitutive absence of Langerin⁺ dermal DCs⁷³, contact hypersensitivity responses develop normally indicating that, at least in the setting of a constitutive absence of Langerin⁺ dermal DCs, these cells are not required for contact hypersensitivity.

A major obstacle to untangling the functions of skin-resident DCs during contact hypersensitivity is the high degree of experimental variability that is intrinsic to the contact hypersensitivity assay. In addition, it is difficult to efficiently examine hapten-specific responses. In the setting of skin infections, however, the functional distinction between skin DC subsets is clearer. Langerin⁺ dermal DCs isolated from skin-draining lymph nodes during recurrent Herpes simplex virus infection efficiently cross-prime antigen-specific CD8⁺ T cells in vitro⁹². In contrast, other skin-resident DCs and lymph node-resident DCs are much less efficient. Similarly, skin infection with Candida albicans induces efficient activation of CD8⁺ T cells in vivo in Langerin-DTA mice, which lack Langerhans cells, but CD8⁺ T cell activation is defective in infected Batf3−/− mice, which lack Langerin⁺ dermal DCs⁹³. Moreover, Langerin⁺ dermal DCs are required for T_H1 cell differentiation in response to C. albicans infection, whereas Langerhans cells are required for the development of T_H17 cell responses. Thus, Langerin⁺ dermal DCs and Langerhans cells are clearly functionally distinct in the setting of skin infection. This may also be true for CHS but its demonstration requires the development of new tools to analyze hapten-specific responses.

Mast Cells

Mast cells are hematopoetically derived cells that reside long-term in barrier tissue sites, such as skin and gut. Mast cells express the high affinity receptor for IgE, FcεRI, and can be activated via antigen-mediated cross-linking of surface IgE (Figure 3a). In addition, mast cells express TLRs and respond to many microbial products⁹⁴. In response to IgE-mediated activation, mast cells induce an immediate wheal and flare response (within minutes) by releasing pre-formed granules that contain a wide variety of immunologically active compounds, such as histamine, proteases, proteoglycans and TNF. Mast cells also secrete a number of pro-inflammatory ‘late’ mediators, such as IL-3, IL-4, IL-5, IL6, IL-8, IL-9, IL-11, IL-13, TNF, CCL3 (also known as MIP-1α), CCL4 (also known as MIP-1β) and CCL2 (also known as MCP1).

Though the participation of mast cells in the development of immune responses against pathogens has been well described (recently reviewed ⁹⁵), the importance of mast cells during contact hypersensitivity is quite controversial. Early work found that mast cells were both redundant and required for contact hypersensitivity ^{96, 97}. More recently, mast cell activation by hapten-specific IgM and complement has been shown to participate in the elicitation phase of contact hypersensitivity⁹⁸. In addition, mast cell activation has been shown to induce migration of skin-resident DCs and to enhance the efficacy of immunizations^{99, 100}. The availability of mice that lack mast cells due to mutations in the kit gene (that is, B6Kit^W-sh/W-sh or WBB6F1-Kit^W/Wv strains) has greatly facilitated evaluation of mast cell function in vivo¹⁰¹. These mast cell-deficient mice can be reconstituted with in vitro-derived mast cells derived from mice deficient in a particular cytokine, thereby functionally generating mice with a mast cell-specific cytokine deletion. Contact hypersensitivity responses to FITC are defective in B6Kit^W-sk/W-sh mice. Reconstitution of these mice with mast cells derived from wild-type mice, but not from TNF-deficient mice, restores contact hypersensitivity¹⁰². Similarly, contact hypersensitivity to oxazalone is defective in WBB6F1-Kit^W/Wv mice as well as in both IgE^−/− and IgE receptor-deficient mice¹⁰³. Thus, mast cells, mast cell activation via FcεRI, and mast cell-derived TNF are required for induction of contact hypersensitivity. Intriguingly, contact hypersensitivity to urushiol in B6Kit^W-sh/W-sh develops normally but fails to appropriately resolve resulting in increased ear swelling compared with wild-type mice several days after challenge. Reconstitution with wild-type, but not IL-10^−/− mast cells, rescues the phenotype¹⁰⁴. These experiments suggest that, at least in response to urushiol, mast cells also suppress the late phase of the contact hypersensitivity response by producing IL-10.

An important caveat to experiments using kit mutant mice is that these mice also have other defects. WBB6F1-Kit^W/Wv mice develop macrocystic anemia, have reduced numbers of neutrophils, lack melanocytes and are sterile ¹⁰⁵. Though B6Kit^W-sh/W-sh mice have a milder phenotype, subtle effects outside the mast cell compartment cannot be excluded. Recently, transgenic mice have been engineered that have mast cell-specific expression of Cre recombinase (Mcpt5-Cre)¹⁰⁶. Breeding Mcpt5-Cre mice with inducible-DTR mice, which ubiquitously express a loxP-stop-diphtheria toxin receptor construct, creates a mouse strain in which mast cells can be ablated by injection of diphtheria toxin ¹⁰⁷. Mast cell ablation prior to sensitization or elicitation impairs contact hypersensitivity responses to FITC and oxazalone. In addition, Mcp5-Cre IL-10^flox mice do not develop exaggerated contact hypersensitivity. Thus, mast cells are required for contact hypersensitivity, but mast cell-derived IL-10 does not appear to be necessary for the resolution of the contact hypersensitivity response. Interestingly, similar to earlier data using urushiol, late contact hypersensitivity responses to hapten are increased in B6Kit^W-sk/W-sh mice but this result is not due to the absence of mast cells, but rather from a previously unrecognized neutrophil defect in B6Kit^W-sk/W-sh mice.

γδ T cells

Dendritic epidermal T cells (DETC) that express the identical γδ TCR (Vγ5/Vδ 1 ) populate the epidermis of virtually all strains of inbred mice but are not found in other tissues. Their location in the epidermis brings them into contact with hapten during the sensitization stage of contact hypersensitivity. It is unknown whether they directly sense the presence of hapten, but they do respond to stress-induced molecules expressed by keratinocytes; for example, DETCs recognize RAE1 via NKG2D¹⁰⁸. Several studies have suggested that these cells participate in contact hypersensitivity by modulating the response of αβ T cells¹⁰⁹. However, TCR δ ^−/− mice, which lack all γδ T cells, develop normal contact hypersensitivity on a C57BL/6 genetic background. Interestingly, TCRδ ^−/− mice on either the FVB or NOD genetic backgrounds develop spontaneous dermatitis and enhanced contact hypersensitivity responses that can be rescued by the adoptive transfer of Vγ5/Vδ 1⁺ T cells, but not by transfer of other γδ T cellsthat do not express Vγ5/Vδ 1¹¹⁰. Due to a point mutation in a gene involved in the intrathymic positive selection of Vγ5/Vδ 1⁺ cells prior to their migration to the skin, the epidermis of the substrain of FVB mice produced by Taconic Farms (FVBTac mice) lacks Vγ5/Vδ 1⁺ DETCs and is instead populated by Vγ5/Vδ 1⁻ DETCs. DETCs in FVBTac mice are functionally defective and these mice exhibit spontaneous dermatitis and develop exaggerated contact hypersensitivity responses that are similar to those seen in TCR δ −/− mice¹¹¹. Thus, Vγ5/Vδ 1⁺ DETCs appear to suppress contact hypersensitivity through still poorly understood mechanisms. γδ T cells are also found in human skin and may be the functional equivalent of the rodent invariant epidermal γδ T cells¹¹².