Dendritic Epidermal T Cells Research Articles

Migration of Tissue Dendritic cells in Immune‐mediated Inflammatory Diseases: Role of Cooperative Interaction Between Epidermal gd T Cells and Skin Dendritic Cells

The skin‐resident dendritic cells (DC), namely dermal DC (dDC) and Langerhans cells (LC), are believed to sample antigens in the skin and migrate to cutaneous lymph nodes (CLN) to induce immunity or tolerance to these antigens. We report a previously unappreciated defect in the migration of LC prior to the appearance of skin inflammation in genetically autoimmune‐prone MRL‐Faslpr/lpr and MRL‐Fas+/+ mice. In these mice, LC displays a drastic reduction in migration in the steady state as well as upon in vitro or in vivo stimulation. This defect is associated with markedly reduced numbers of γδ dendritic epidermal T cells (DETC) in the epidermis of MRL mice. The role of DETC is not fully investigated but they are believed to be involved in homeostasis of skin, and facilitate wound healing. Both defects are corrected and skin inflammation is reduced by in vivo treatment of these animals with α‐galactosylceramide, a glycolipid that binds CD1d and activates natural killer T (NKT) cells. Surprisingly, DETC numbers and LC migration are also reduced in CD1d‐deficient, but not in NKT cell‐deficient, mice. These data suggest that a glycolipid can induce expansion of skin γδ DETC, which promote the migration of LC from epidermis to skin draining lymph node.

Protective Effects of Cyclooxygenase‐2 Inhibitors on Narrow‐band Ultraviolet B‐irradiated Epidermal Ia+ Langerhans Cells and Thy‐1+ Dendritic Epidermal T Cells in Mice†

Cyclooxygenase (COX)-2 inhibitors are known to be used as chemopreventative agents against certain malignancies. Thus far, there has been very limited information on whether COX-2 inhibitors protect against chronic narrow-band UVB (NB-UVB)-induced immunosuppression. The present study investigated the effect of nonselective and specific COX-2 inhibitors, indomethacin and celecoxib, on epidermal Ia+ Langerhans cells (LCs) and Thy-1+ dendritic epidermal T cells (DETCs) in mice irradiated with NB-UVB. Sixty female BALB/c mice were divided randomly into the control group (sham) and the experimental groups (irradiated with NB-UVB for 17 weeks, further divided into five groups according to the diets containing different concentrations of either COX-2 inhibitors). Alterations in the density and morphology of epidermal Ia+ LCs and Thy-1+ DETCs in mice were documented using fluorescence microscopy. Chronic NB-UVB irradiation substantially decreased the density and altered the morphology of the epidermal Ia+ LCs and Thy-1+ DETCs in control mice. The dietary supplementation of both COX-2 inhibitors displayed a dosage-dependent protective effect on the murine dendritic cells irradiated by NB-UVB. In conclusion, COX-2 inhibitors protected against chronic NB-UVB-induced density and morphologic changes in epidermal Ia+ LCs and Thy-1+ DETCs in mice.

γδ T cells: firefighters or fire boosters in the front lines of inflammatory responses

Intradermal inoculation of cloned self-reactive alphabeta T cells into the footpads of mice induced cutaneous graft-versus-host disease (GVHD), and after recovery from GVHD, the epidermis became resistant to subsequent attempts to induce GVHD. Resistance to GVHD was not induced in the epidermis of T-cell receptor delta-deficient (TCRdelta(-/-)) mice that lacked gammadelta T cells bearing canonical Vgamma5/Vdelta1(+)gammadeltaTCRs, known as dendritic epidermal T cells (DETCs), and resistance was restored by reconstitution of these mutant mice with precursors of Vgamma5(+) DETCs. Pulmonary infection by Cryptococcus neoformans induced an increase of gammadelta T cells in the lung, and in comparison with wildtype mice, TCRdelta(-/-) mice eliminated C. neoformans more rapidly and synthesized more interferon-gamma in the lung. In the mouse small intestine, the absence of gammadelta T cells is associated with a reduction in epithelial cell turnover and downregulation of the expression of major histocompatibility complex class II molecules. The protective role of gammadelta T cells was verified in a dextran sodium sulfate-induced inflammatory bowel disease (IBD) model, whereas in a spontaneous model of IBD, gammadelta T cells were involved in the exacerbation of colitis in TCRalpha(-/-) mice. Taken together, in addition to the homeostatic regulation of epithelial tissues, gammadelta T cells appear to play a pivotal role in the modification of inflammatory responses induced in many organs containing epithelia.

Runx3 regulates dendritic epidermal T cell development

The Runx3 transcription factor regulates development of T cells during thymopoiesis and TrkC sensory neurons during dorsal root ganglia neurogenesis. It also mediates transforming growth factor-β signaling in dendritic cells and is essential for development of skin Langerhans cells. Here, we report that Runx3 is involved in the development of skin dendritic epidermal T cells (DETCs); an important component of tissue immunoregulation. In developing DETCs, Runx3 regulates expression of the αEβ7 integrin CD103, known to affect migration and epithelial retention of DETCs. It also regulates expression of IL-2 receptor β (IL-2Rβ) that mediates cell proliferation in response to IL-2 or IL-15. In the absence of Runx3, the reduction in CD103 and IL-2Rβ expression on Runx3 −/− DETC precursors resulted in impaired cell proliferation and maturation, leading to complete lack of skin DETCs in Runx3 −/− mice. The data demonstrate the requirement of Runx3 for DETCs development and underscore the importance of CD103 and IL-2Rβ in this process. Of note, while Runx3 −/− mice lack both DETCs and Langerhans cells, the two most important components of skin immune surveillance, the mice did not develop skin lesions under pathogen-free (SPF) conditions.

Cells of cutaneous immunity in Xenopus: Studies during larval development and limb regeneration

The anuran Xenopus laevis is an experimental model for vertebrate development, immunology, and regenerative biology. Using histochemistry and immunohistochemistry (IHC) we examined embryonic, larval, and postmetamorphic Xenopus skin for the presence of dendritic cells (DCs), Langerhans cells (LCs), and dendritic epidermal T cells (DETCs), all components of cutaneous immunity that have been implicated in skin repair and regeneration. Cells expressing three markers for dendritic and Langerhans cells (formalin-resistant ATPase activity, major histocompatibility complex [MHC] class II antigens, and vimentin) and having morphology like that of these cells first appeared during late embryonic stages, becoming abundant by prometamorphosis. Cells positive for these markers were also numerous in the wound epithelia of regenerating hindlimbs at both early and late larval stages. Cells tentatively identified as DETCs were found, beginning at early larval stages, using IHC with antibodies against heterologous CD3 ε chain and T-cell receptor δ. Further characterization and work with the putative DCs, LCs, and DETCs demonstrated here will allow not only greater understanding of the amphibian immune system, but also further elucidation of regenerative growth and scarring.

T cells developing in fetal thymus of T‐cell receptor α‐chain transgenic mice colonize γδ T‐cell‐specific epithelial niches but lack long‐term reconstituting potential

The gammadelta T cells generated during mouse fetal development are absolutely dependent on their invariant T-cell receptors (TCRs) for their function. However, there is little information on whether the epithelial homing properties of fetal T cells might also be developmentally induced by factors unrelated to TCR specificity. We have previously described TCR alpha-chain transgenic (2B4 TCR-alpha TG) mice, in which the transgenic TCR alpha-chain is expressed early, already at embryonic day 14 (E14). These mice have a large population of 'gammadelta T-cell-like' CD4- CD8- (double-negative; DN) alphabeta T cells, some of which develop during E14-E18 contemporarily to intraepithelial lymphocytes (IELs) expressing invariant TCR-gammadelta. Using the 2B4 TCR-alpha TG mouse model we have been able to more precisely study the impact of a variant TCR expression on IEL development and homing. In this study we show that TCR-alpha TG and TCR-alpha TG crossed to TCR-delta-deficient mice (TCR-alpha TG x TCR-delta-/-) carry TG TCR-alpha+ dendritic epidermal T cells (DETCs) and TCR-alpha TG+ IELs in the small intestine. The TG+ DETCs develop and seed the epidermis with similar kinetics as Vgamma5+ DETCs of normal mice, in contrast to the TCR-alphabeta+ DETCs found in TCR-delta-/- mice. However, whereas the intestinal TCR-alpha TG+ IELs persist in old mice (> 20 months), the TCR-alpha TG+ DETCs do not. The data in this study indicate that the timing of TCR expression and thereby development during ontogeny regulates the specific homing potential for fetal T cells but not their subsequent functions and properties.

NKG2D Ligation without T Cell Receptor Engagement Triggers Both Cytotoxicity and Cytokine Production in Dendritic Epidermal T Cells

NKG2D is an activating receptor that recognizes self-ligands induced on stressed, infected, or transformed cells. In mice, two NKG2D isoforms (NKG2D-S (short) and NKG2D-L (long)) that associate differentially with DAP10 and DAP12 adaptor proteins exist. Differential expression of these isoforms and adaptor proteins depending on the activating state and cell types determines distinct functional outcomes of NKG2D ligation: direct activation of cytotoxicity in natural killer (NK) cells and cytokine production in activated NK cells, but only costimulation in activated CD8+ T cells. Intraepithelial gammadelta T cells of the mouse skin, termed dendritic epidermal T cells (DETCs), were also shown to express NKG2D, but the NKG2D isoform(s) expressed in DETCs have not been determined. Furthermore, functional outcomes of NKG2D ligation in DETCs are largely unknown, although costimulation of DETC-mediated cytotoxicity by NKG2D was demonstrated. Here, we show that DETCs constitutively express NKG2D-S, NKG2D-L, DAP10, and DAP12 transcripts as well as cell surface NKG2D protein. Blocking of NKG2D inhibited DETC-mediated cytotoxicity against target cells that do not express T cell receptor ligands. Cross-linking of NKG2D on DETCs induced IFN-gamma production. These findings demonstrate that DETCs constitutively express NKG2D that acts as a primary activating receptor, and indicate its important role in cutaneous immune surveillance.

Environmentally Responsive and Reversible Regulation of Epidermal Barrier Function by γδ T Cells

The intraepithelial lymphocyte (IEL) network possibly composes the largest T-cell compartment in the body, but it is poorly understood. IELs show limited T-cell receptor (TCR) diversity and have been proposed to respond to generic stress signals rather than pathogen-specific antigens. Consistent with this, skin-resident TCRgammadelta+ cells, known as dendritic epidermal T cells (DETC), downregulate cutaneous inflammation, promote wound healing, and protect against cutaneous neoplasia. These pleiotropic effects collectively suggest that DETC (and IEL more generally) may contribute to epithelial maintenance and barrier function. The present studies test this hypothesis. Using skin surface impedance analysis to measure hydration status and transepidermal water loss, we show that the epidermal barrier is defective in gammadelta T-cell deficient mice. However, this does not represent a constitutive role of gammadelta cells, but rather one that is dependent on environmental challenge, consistent with the primary role for lymphocytes being the response of the host to its environment. Likewise, the importance of the physiologic DETC-associated TCR is demonstrated by showing that Vgamma5+ fetal thymocytes reconstitute the barrier function defect in TCRdelta-/- mice, while Vgamma5-/- mice also show environmentally responsive defects in cutaneous physiology.

Identification of Novel γδ T-Cell Subsets following Bacterial Infection in the Absence of Vγ1+T Cells: Homeostatic Control of γδ T-Cell Responses to Pathogen Infection by Vγ1+T Cells

Although gammadelta T cells are a common feature of many pathogen-induced immune responses, the factors that influence, promote, or regulate the response of individual gammadelta T-cell subsets to infection is unknown. Here we show that in the absence of Vgamma1+ T cells, novel subsets of gammadelta T cells, expressing T-cell receptor (TCR)-Vgamma chains that normally define TCRgammadelta+ dendritic epidermal T cells (DETCs) (Vgamma5+), intestinal intraepithelial lymphocytes (iIELs) (Vgamma7+), and lymphocytes associated with the vaginal epithelia (Vgamma6+), are recruited to the spleen in response to bacterial infection in TCR-Vgamma1-/- mice. By comparison of phenotype and structure of TCR-Vgamma chains and/or -Vdelta chains expressed by these novel subsets with those of their epithelium-associated counterparts, the Vgamma6+ T cells elicited in infected Vgamma1-/- mice were shown to be identical to those found in the reproductive tract, from where they are presumably recruited in the absence of Vgamma1+ T cells. By contrast, Vgamma5+ and Vgamma7+ T cells found in infected Vgamma1-/- mice were distinct from Vgamma5+ DETCs and Vgamma7+ iIELs. Functional analyses of the novel gammadelta T-cell subsets identified for infected Vgamma1-/- mice showed that whereas the Vgamma5+ and Vgamma7+ subsets may compensate for the absence of Vgamma1+ T cells by producing similar cytokines, they do not possess cytocidal activity and they cannot replace the macrophage homeostasis function of Vgamma1+ T cells. Collectively, these findings identify novel subsets of gammadelta T cells, the recruitment and activity of which is under the control of Vgamma1+ T cells.

Characterization of CD200-Receptor Expression in the Murine Epidermis

CD 200 is a widely expressed transmembrane glycoprotein that transmits an inhibitory signal after ligation of the structurally homologous CD 200-receptor-1 (CD 200 R1). Recently, we showed that CD 200 is expressed on keratinocytes and plays a role in protecting hair follicles from autoimmune attack. Here, we report the characterization of cell surface and mRNA expression of CD 200 R1 by cells of the murine epidermis. In addition, we report mRNA expression for other members of the CD 200 R-family (R2-R4) by quantitative real-time RT-PCR. Variable levels of CD 200 R1, R2, R3, and R4 mRNA were detected in bulk epidermal cell suspensions. Freshly isolated Langerhans cells (LC) preferentially expressed CD 200 R1. Consistent with an inhibitory role for CD 200:CD 200 R1 interaction, LC obtained from mice deficient in CD 200 (CD 200(-/-)) were in a heightened state of activation as compared with wild-type (CD 200(+/+)) cells. Freshly isolated dendritic epidermal T cells (DETC) expressed low levels of CD 200 R1, R2, and R3 mRNA, but they preferentially increased cell surface and mRNA expression of CD 200 R1 upon activation in vitro. In functional assays using sub-optimal CD3 signaling, immobilized CD 200 inhibited DETC proliferation and cytokine secretion. Collectively, these results suggest that CD 200:CD 200 R interactions may play a role in regulating both LC and DETC in cutaneous immune reactions.

Zeta‐chain‐associated protein‐70 molecule is essential for the proliferation and the final maturation of dendritic epidermal T cells

Adult murine epidermis contains members of the epithelial gammadelta T-cell family called dendritic epidermal T cells (DETCs). Their development and maturation have been the subjects of investigations, but the details are still unclear. T-cell receptor (TCR) zeta-chain-associated protein-70 (ZAP-70), one of the protein tyrosine kinases required for TCR signaling, plays a pivotal role in the development of alphabeta T cells. In mice lacking ZAP-70, thymic development of alphabeta T cells was completely arrested at the immature CD4(+)CD8(+) TCR(low) stage. Here, we examined whether or not the development and maturation of DETCs were altered in ZAP-70-deficient mice. Immunohistochemical analyses of epidermal sheets revealed that the number of DETCs was reduced and their characteristic dendrites were lost or markedly shortened in ZAP-70(-/-) mice. In flow cytometric analyses, the expression levels of gammadelta TCR and Thy-1.2 on the ZAP-70(-/-) DETCs were lower than those on ZAP-70(+/-) DETCs. The expression of a very early activation antigen, CD69, was not detected on ZAP-70(-/-) DETCs, whereas CD69 was expressed on ZAP-70(+/-) DETCs. Furthermore, ZAP-70(-/-) DETCs showed markedly reduced proliferation and no IL-2 gene expression in response to anti-CD3epsilon or concanavalin A stimulation. These results suggest that ZAP-70 is essential for TCR signaling which induces the proliferation and the final maturation of DETCs in the epidermis.

Vitamin D receptor ablation alters skin architecture and homeostasis of dendritic epidermal T cells

1alpha,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], the active metabolite of vitamin D, exerts its activities by binding to the vitamin D receptor (VDR) with subsequent function as a transcription factor. Targeted ablation of the VDR in mice results in rickets and alopecia. To study the consequences of VDR deficiency for skin physiology, and to investigate the mechanisms of the immunosuppressive effect of 1,25(OH)(2)D(3) on LC. We studied the structural, phenotypic and functional properties of skin and individual skin leucocyte populations in VDR(-/-) mice. The lack of VDR induced a wide spectrum of pathologies including dermal deposition of collagen, enlargement of sebaceous glands, dilation of the hair follicles, development of epidermal cysts, increased numbers of dendritic epidermal T cells (DETC) and hyperkeratosis. Ageing aggravated these changes. Intriguingly, Langerhans cells (LC) were indistinguishable in distribution, morphology and number compared with controls. In vitro, LC underwent a maturation/migration process similar to LC from control mice. Pretreatment of epidermal cells or LC-enriched epidermal cell suspensions with 1,25(OH)(2)D(3) impaired LC maturation and T-cell stimulatory capacity from VDR(+/+) but not VDR(-/-) mice, demonstrating that LC are targets of vitamin D(3) and that interaction between vitamin D(3) and LC results in a suppression of LC activity. Our data imply that VDR expression controls dermal collagen production, hair development and growth, proliferation of sebaceous glands and the homeostasis of DETC. Surprisingly, VDR deficiency does not influence LC phenotype and function.

Dendritic Epidermal T-Cell Activation

Although gammadelta T cells compose a small proportion of lymphocytes in lymphoid compartments and peripheral blood, they are the major T-cell population present in epithelial tissues. However, the role played by gammadelta TCR expressing intraepithelial lymphocytes (IEL) has been enigmatic. The location of tissue-resident IEL suggests that they are important members of the first line of defense against insult for organs exposed to the environment, including the skin, gut, lungs, and reproductive system. Dendritic epidermal T cells (DETC) are the skin-resident gammadeltaIEL and serve as a model system for gammadeltaIEL in other locations. DETC have demonstrated importance in the modulation of immune responses, surveillance and repair of tissue, and resistance to infection. This work discusses recent developments in understanding DETC activation.

Up-regulation of cell surface Toll-like receptor 4-MD2 expression on dendritic epidermal T cells after the emigration from epidermis during cutaneous inflammation

Mouse epidermis contains a population of gammadelta T cells, termed dendritic epidermal T cells (DETCs), which uniformly express the invariant Vgamma3 T cell receptor. Certain DETC lines were reported to respond to Gram-negative bacteria in the presence of immobilized anti-CD3 monoclonal antibody or to lipopolysaccharide (LPS) in the presence of B cell lines. To determine whether DETCs express the primary signaling receptor for LPS, Toll-like receptor (TLR) 4-MD2. We analyzed expression of TLR4-MD2 in three independent DETC lines as well as in freshly isolated DETCs. All DETC lines expressed TLR4 and MD2 transcripts and TLR4-MD2 protein complex intracellularly, but none expressed TLR4-MD2 on the cell surface. By immunoblotting, only the immature form of TLR4 protein was detected in the DETC lines. The DETC lines did not respond to LPS even in the presence of immobilized anti-CD3 monoclonal antibody. Freshly isolated DETCs and their fetal thymic precursors also lacked cell surface expression of TLR4-MD2, but a small subpopulation of dermal Vgamma3 T cells isolated from croton oil-painted skin expressed TLR4-MD2 on the cell surface. Similarly, Vgamma3 T cells emigrated from organ-cultured epidermis expressed cell surface TLR4-MD2. These results demonstrate that DETCs do not constitutively express cell surface TLR4-MD2, but TLR4-MD2 expression may be up-regulated when DETCs emigrate from epidermis during cutaneous inflammation.

Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1

A fine balance between rates of proliferation and apoptosis in the skin provides a defensive barrier and a mechanism for tissue repair after damage. Vgamma3(+) dendritic epidermal T cells (DETCs) are primary modulators of skin immune responses. Here we show that DETCs both produce and respond to insulin-like growth factor 1 (IGF-1) after T cell receptor stimulation. Mice deficient in DETCs had a notable increase in epidermal apoptosis that was abrogated by the addition of DETCs or IGF-1. Furthermore, DETC-deficient mice had reduced IGF-1 receptor activation at wound sites. These findings indicate critical functions for DETC-mediated IGF-1 production in regulating skin homeostasis and repair.

Regulation of skin cell homeostasis by gamma delta T cells.

Although innate T lymphocytes such as gamma delta T cells have been extensively studied, their biological role has remained an enigma to researchers for many years. However, recent advances have begun to explain their complex role in the immune system. Gamma delta T cells are often the major T cell population in epithelial tissues such as the skin, gut, and lung where they have been implicated in maintaining tissue integrity, defending against pathogens, and regulating inflammation. The gamma delta T cells that reside in the skin are a prototypical intra-epithelial lymphocyte (IEL) population. These skin gamma delta T cell receptor (TCR)-expressing cells are named dendritic epidermal T cells (DETC) for their unique dendritic morphology. Using their gamma delta TCR, DETC recognize an unknown ligand expressed by stressed or damaged keratinocytes. Activated DETC exhibit effector functions such as cytokine production, cytolysis, and proliferation in vitro. Recent findings have shown that upon activation by damaged keratinocytes, DETC produce a key keratinocyte growth factor for wound repair called fibroblast growth factor 7 (FGF-7). FGF-7 is produced in vitro and in vivo, suggesting that DETC might play an important role in the biological function of wound repair. Indeed a delay in wound closure and a decrease in the proliferation of keratinocytes at the wound site have been observed in mice lacking gamma delta T cells. In addition to effector functions attributed to DETC, it has also been suggested that gamma delta T cells such as DETC have regulatory roles such as initiating or inhibiting inflammation. This is supported by the findings that DETC produce chemokines and cytokines. Control of the inflammatory response in the epithelium may provide another mechanism to reestablish homeostasis after a biological insult such as wound infliction. Understanding the function of DETC may be useful in the development of future therapies for chronic wounds and the maintenance of skin homeostasis.

Anti-inflammatory effects in the skin of thymosin-beta4 splice-variants.

The intraepithelial lymphocyte (IEL) network of T-cell receptor gammadelta+ (Vgamma5+) dendritic epidermal T cells (DETC) in murine skin down-regulates cutaneous inflammation, although the mechanism is unknown. Thymosin-beta4 (Tbeta4), identified by serial analysis of gene expression as a predominant transcript in gut IEL, encodes both a ubiquitous actin-binding protein (UTbeta4) with demonstrated capacity to inhibit neutrophilic infiltration, and a splice-variant limited to lymphoid tissue (LTbeta4) with unknown bioactivity. Freshly isolated Vgamma5+ DETCs expressed both forms, while only LTbeta4 was preferentially up-regulated after cellular activation in vitro. To compare the anti-inflammatory properties of LTbeta4 and UTbeta4 in the skin in vivo, the biological activities of synthesized polypeptides were assessed using three different strategies: neutrophil infiltration by footpad lambda-carrageenan injection; irritant contact dermatitis to 12-O-tetradecanoylphorbol 13-acetate; and allergic contact dermatitis to 2,4-dinitrofluorobenzene. These studies clearly showed that the anti-inflammatory activities of LTbeta4 were broader and most often stronger than those of UTbeta4. Thus, the activation-responsive expression of the lymph-specific form of Tbeta4 may be one mechanism by which DETC, and possibly other IELs, down-regulate local inflammation.

Developmental and functional defects of thymic and epidermal V gamma 3 cells in IL-15-deficient and IFN regulatory factor-1-deficient mice.

In this study, the role of IL-15 and its regulation by the transcription factor IFN regulatory factor-1 (IRF-1) in murine V gamma 3 T cell development and activity is assessed. Compared with wild-type (WT) mice, reduced numbers of mature V gamma 3 cells were found in the fetal thymus of IL-15(-/-) mice, while IRF-1(-/-) mice displayed normal frequencies. V gamma 3(+) dendritic epidermal T cells (DETCs) were absent in IL-15(-/-) mice but present in IRF-1(-/-) mice. DETCs from IRF-1(-/-) mice displayed morphologically a less mature phenotype and showed different emergence kinetics during ontogeny. This corresponded with lower IL-15 mRNA levels in the skin epidermis. Comparable levels of IL-7 were found in the skin of WT and IL-15(-/-) mice. Adoptive transfer experiments of WT fetal thymocytes into IL-15(-/-) mice did not result in the development of V gamma 3(+) DETCs, confirming the nonredundant role of IL-15 in the skin during DETC development. In vitro, cytolytic activity of IL-15(-/-) V gamma 3 cells was normal after stimulation with IL-15 and was further enhanced by addition of IL-12. In contrast, cytolytic activity of IRF-1(-/-) V gamma 3 cells remained defective after stimulation with IL-15 in combination with IL-12. These data suggest that IL-15 is redundant for the development and/or survival of mature V gamma 3 cells in the fetal thymus, whereas it is essential for the localization of V gamma 3 cells in the skin. Furthermore, a possible role for IRF-1 in inducing morphological maturation of DETCs and cytolytic capacity of V gamma 3 cells is suggested.

A role for skin gammadelta T cells in wound repair.

Gammadelta T cell receptor-bearing dendritic epidermal T cells (DETCs) found in murine skin recognize antigen expressed by damaged or stressed keratinocytes. Activated DETCs produce keratinocyte growth factors (KGFs) and chemokines, raising the possibility that DETCs play a role in tissue repair. We performed wound healing studies and found defects in keratinocyte proliferation and tissue reepithelialization in the absence of wild-type DETCs. In vitro skin organ culture studies demonstrated that adding DETCs or recombinant KGF restored normal wound healing in gammadelta DETC-deficient skin. We propose that DETCs recognize antigen expressed by injured keratinocytes and produce factors that directly affect wound repair.

Seeding of dendritic epidermal T cells in the neonatal skin is reduced in 129 strain of mice

Precursors for Thy-1 + dendritic epidermal T cells (DETC) develop as Vγ3 + T cells in the fetal thymus and become distributed in the adult skin. DETC are variably distributed from site to site and from strain to strain. To elucidate the basis of strain variation, we first compared the density of DETC in the ear epidermis among different mouse strains. In the ear epidermis, we detected the highest level of DETC in C57BL/6 mice, intermediate levels in C3H and CBA/J mice, and the lowest levels in other strains including BALB/c and 129 mice. Although BALB/c and 129+Ter/Sv mice showed higher levels of DETC in the abdomen than in the ear, the levels were significantly lower than C57BL/6 mice. Furthermore, in neonatal abdominal epidermis we detected considerably lower numbers of DETC in BALB/c and 129+Ter/Sv mice than in C57BL/6 mice. In contrast, Vγ3 + DETC precursors in the fetal thymus are rather increased in 129+Ter/Sv mice. These results suggest that fewer DETC precursors are seeded in the neonatal skin of BALB/c and 129+Ter/Sv mice and that their expansion in the skin during neonatal to adult stages does not reach the levels in C57BL/6 mice.