Dermal-Resident versus Recruited γδ T Cell Response to Cutaneous Vaccinia Virus Infection (original) (raw)
Dermal γδ T cells - What have we learned?
Cellular immunology, 2015
Over the last several years, a number of papers have called attention to a distinct population of γδ T cells preferentially found in the dermis of the skin of normal mice. These cells appear to play an important role in promoting the development of psoriasis, but also are critical for host resistance to particular pathogens. They are characterized by the expression of a limited subset of γδ T cell receptors and a strong propensity to secrete IL-17. Perhaps most importantly, humans appear to carry an equivalent dermal γδ T cell population, likewise biased to secrete IL-17 and also implicated as playing a pathogenic role in psoriasis. This review will attempt to summarize and reconcile recent findings concerning the dermal γδ T cells.
Environmentally Responsive and Reversible Regulation of Epidermal Barrier Function by γδ T Cells
Journal of Investigative Dermatology, 2006
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 TCRgd þ 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 gd T-cell deficient mice. However, this does not represent a constitutive role of gd 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 Vg5 þ fetal thymocytes reconstitute the barrier function defect in TCRd À/À mice, while Vg5 À/À mice also show environmentally responsive defects in cutaneous physiology.
Cutaneous immunosurveillance by self-renewing dermal T cells
Journal of Experimental Medicine, 2011
Decreased CD4 + T cell expansion is related to a reduction in neutrophil recruitment to the skin and decreased BCG shuttling to draining lymph nodes. Thus, dermal T cells are an important part of the resident cutaneous immunosurveillance program. Our data demonstrate functional specialization of T cells in distinct microcompartments of the skin.
Resident Skin-specific γδ T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation
Journal of Experimental Medicine, 2002
The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) γδ+ (Vγ5+) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in γδ T cells (δ−/− mice), and in δ−/− mice reconstituted with DETC or with different γδ cell subpopulations. NOD.δ−/− and FVB.δ−/− mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6.δ−/− strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD.δ−/− mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB.δ−/−, but not in C57BL/6.δ−/− mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.β−/− δ−/− mice lacking all T cells, indicating that αβ T cell–mediated inflammation is the target for γδ-mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant de...
Homogeneous epithelial γδ T cell repertoire of the skin is shaped through peripheral selection
Journal of Dermatological Science, 2001
In contrast to the T cell receptor (TCR) diversity of major hi T cells in lymphoid tissues, epithelial T cells of the murine skin, called dendritic epidermal T cells (DETC), express exclusively an invariant kl TCR. Fetal thymic precursors of DETC immigrate to the skin before birth, and in adult mice T cells expressing the canonical kl TCR identical to that of DETC are not found in other lymphoid or epithelial tissues. Here, we show that DETC precursors migrate to the gut as well as to the skin during fetal periods, but preferentially survive and expand in the skin after birth. We propose that similar to the thymic selection of the diverse hi T cell repertoire, 'peripheral selection' of the homogeneous epithelial kl T cell repertoire may be mediated by TCR signaling upon the recognition of the self-ligand, because the ligand for the DETC TCR was expressed only in the skin.
Tissue-resident T cells: dynamic players in skin immunity
Frontiers in immunology, 2014
The skin is a large and complex organ that acts as a critical barrier protecting the body from pathogens in the environment. Numerous heterogeneous populations of immune cells are found within skin, including some that remain resident and others that can enter and exit the skin as part of their migration program. Pathogen-specific CD8(+) T cells that persist in the epidermis following infection are a unique population of memory cells with important roles in immune surveillance and protective responses to reinfection. How these tissue-resident memory T cells form in the skin, the signals controlling their persistence and behavior, and the mechanisms by which they mediate local recall responses are just beginning to be elucidated. Here, we discuss recent progress in understanding the roles of these skin-resident T cells and also highlight some of the key unanswered questions that need addressing.
Science Translational Medicine, 2015
The skin of an adult human contains about 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice, but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human-engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All nonrecirculating resident memory T cells (T RM ) expressed CD69, but most were CD4 + , CD103 − , and located in the dermis, in contrast to studies in mice. Both CD4 + and CD8 + CD103 + T RM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103 − T RM . T RM of both types had more potent effector functions than recirculating T cells. We observed two distinct populations of recirculating T cells, CCR7 + /L-selectin + central memory T cells (T CM ) and CCR7 + /L-selectin − T cells, which we term migratory memory T cells (T MM ). Circulating skin-tropic T MM were intermediate in cytokine production between T CM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant T CM and T MM induced distinct inflammatory skin lesions, and T MM were depleted more slowly from skin after alemtuzumab, suggesting that T MM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities.
CD4+ T Cell Responses Elicited by Different Subsets of Human Skin Migratory Dendritic Cells
Journal of Immunology, 2005
Skin dendritic cells (DC) are professional APC critical for initiation and control of adaptive immunity. In the present work we have analyzed the CD4 ؉ T cell stimulatory function of different subsets of DC that migrate spontaneously from human skin explants, including CD1a ؉ CD14 ؊ Langerhans' cells (LC), CD1a ؊ CD14 ؊ dermal DC (DDC), and CD1a ؊ CD14 ؉ LC precursors. Skin migratory DC consisted of APC at different stages of maturation-activation that produced IL-10, TGF-1, IL-23p19, and IL-12p40, but did not release IL-12p70 even after exposure to DC1-driving stimuli. LC and DDC migrated as mature/activated APC able to stimulate allogeneic naive CD4 ؉ T cells and to induce memory Th1 cells in the absence of IL-12p70. The potent CD4 ؉ T cell stimulatory function of LC and DDC correlated with their high levels of expression of MHC class II, adhesion, and costimulatory molecules. The Th1-biasing function of LC and DDC depended on their ability to produce IL-23. By contrast, CD1a ؊ CD14 ؉ LC precursors migrated as immature-semimature APC and were weak stimulators of allogeneic naive CD4 ؉ T cells. However, and opposite of a potential tolerogenic role of immature DC, the T cell allostimulatory and Th1-biasing function of CD14 ؉ LC precursors increased significantly by augmenting their cell number, prolonging the time of interaction with responding T cells, or addition of recombinant human IL-23 in MLC. The data presented in this study provide insight into the function of the complex network of skin-resident DC that migrate out of the epidermis and dermis after cutaneous immunizations, pathogen infections, or allograft transplantation.
Journal of Experimental Medicine, 2002
The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) ␥␦ ϩ (V ␥ 5 ϩ ) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in ␥␦ T cells ( ␦ Ϫ / Ϫ mice), and in ␦ Ϫ / Ϫ mice reconstituted with DETC or with different ␥␦ cell subpopulations. NOD. ␦ Ϫ / Ϫ and FVB. ␦ Ϫ / Ϫ mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6. ␦ Ϫ / Ϫ strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD. ␦ Ϫ / Ϫ mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB. ␦ Ϫ / Ϫ , but not in C57BL/6. ␦ Ϫ / Ϫ mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.  Ϫ / Ϫ ␦ Ϫ / Ϫ mice lacking all T cells, indicating that ␣ T cell-mediated inflammation is the target for ␥␦ -mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant dermatitis in FVB. ␦ Ϫ / Ϫ mice were down-regulated by V ␥ 5 ϩ DETC, but not by epidermal T cells expressing other ␥␦ TCRs. This study demonstrates that functional impairment at an epithelial interface can be specifically attributed to absence of the local TCR-␥␦ ϩ IEL subset and suggests that systemic inflammatory reactions may more generally be subject to substantial regulation by local IELs.
Selection of the cutaneous intraepithelial γδ+ T cell repertoire by a thymic stromal determinant
Nature Immunology, 2006
Intraepithelial lymphocytes constitute a group of T cells that express mainly monospecific or oligoclonal T cell receptors (TCRs). Like adaptive TCRab + T cells, intraepithelial lymphocytes, a subset enriched in TCRcd + T cells, are proposed to be positively selected by thymically expressed self agonists, yet no direct evidence for this exists at present. Mouse dendritic epidermal T cells are prototypic intraepithelial lymphocytes, displaying an almost monoclonal TCRcd + repertoire. Here we describe an FVB substrain of mice in which this repertoire was uniquely depleted, resulting in cutaneous pathology. This phenotype was due to failure of dendritic epidermal T cell progenitors to mature because of a heritable defect in a dominant gene used by the thymic stroma to 'educate' the natural, skin-associated intraepithelial lymphocyte repertoire to be of physiological use.
The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin
Nature Immunology, 2013
Tissue-resident memory T cells (T RM) provide superior protection against infection in extra-lymphoid tissues. Here we show that CD103 + CD8 + T RM cells developed in the skin from killer cell lectin-like receptor G1 (KLRG1)-negative precursors that selectively infiltrate the epithelial layer. A combination of epithelial entry in addition to interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) signaling was required for formation of these long-lived memory cells. Importantly, T RM differentiation resulted in the progressive acquisition of a unique transcriptional profile that differed from those expressed by circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral memory population that forms a first-line immune defense system in barrier tissues.
Immunology, 2000
The repertoire of lymphocyte receptor genes encoded in a germline is further diversi®ed by a number of processes, including the template-independent addition of nucleotides (N regions) by means of terminal deoxynucleotidyl transferase (TdT). Normally, mouse cd T cells in the early fetal thymus, whose T-cell receptor (TCR) genes lack N regions and are encoded by Vc3-Jc1 and Vd1-Dd2-Jd2 with canonical junctions (invariant Vc3Vd1), are thought to be the precursors of dendritic epidermal T cells (DETC). We generated mutant mice whose endogenous TdT promoter was replaced with the lck promoter through homologous recombination. These mutant mice expressed TdT in fetal thymus, had abundant N regions and infrequent canonical junctions in c and d rearrangements, and showed a decreased number of cd T cells. Various Vc3Vd1 T cells, most of which had N regions in their TCR genes, were found to disseminate in the skin of newborn mutant mice, whereas normal numbers of DETCs with the invariant Vc3Vd1 rearrangement were observed in adult mutants. These data demonstrate that the regulation of TdT expression during fetal development is important for the generation of cd T cells, and that Vc3Vd1 T cells, which have various junctional sequences in their TCR genes, randomly disseminate in skin, but invariant Vc3Vd1 T cells have a great advantage for proliferation in skin.
Epithelial defence by γδ T cells
… archives of allergy …, 2005
during intrathymic T cell development, there are only six expressed human V ␥ genes and a similarly small number of V ␦ genes . Nevertheless, the ␥␦ TCR repertoire can be at least as diverse as the ␣ TCR repertoire, due to the tremendous impact of mechanisms such as N nucleotide insertions during TCR gene rearrangement and usage of all three reading frames in the case of D ␦ elements . Interestingly, however, the expressed ␥␦ TCR repertoire is highly biased, resulting in a preferential expression of some V ␥ /V ␦ genes in certain anatomical localizations.
Thy-1+ dendritic epidermal cells belong to the T-cell lineage
Proceedings of the National Academy of Sciences, 1987
The murine epidermis contains a population of dendritic, Thy-l+ cells (Thy-l+ DEC). Although it is now clear that these cells are of bone marrow origin, extensive morphological, histochemical, and cell-membrane marker studies have not definitively placed them in any known hematopoietic differentiation pathway. Based on the observation that Thy-1 DEC can be propagated in vitro with Con A and interleukin 2, we have established three cell lines (Tehy 184, Tehy 245, and Yety 245) that can be continuously grown in medium with lectin-lymphokine-rich culture supernatants of rat spleen cells. With the exception of the loss of reactivity with anti-asialo-GMS antibodies (Tehy 184 and Tehy 245) and the gain of interleukin 2 receptor expression, the cultured cell lines bear the same surface characteristics as freshly isolated Thy-i + DEC: Thy-l+, Ly-5', Lyt-l1, Lyt-2-, L3T4-, la-, sIg-. Using Southern and RNA gel blot analysis, we now demonstrate that these Thy-l+ DEC-derived cell lines exhibit various patterns of rearrangements in the gene complexes encoding the T-cell
Differential Roles of Cytokine Receptors in the Development of Epidermal γδ T Cells
The Journal of Immunology, 2001
IL-7 and IL-15 play important roles in γδ T cell development. These receptors transmit proliferation and/or survival signals in γδ T cells. In addition, the IL-7R promotes recombination and transcription in the TCR γ locus. To clarify the role of the cytokine receptors in the development of epidermal γδ T cells, we introduced a Vγ3/Vδ1 TCR transgene, derived from Thy-1+ dendritic epidermal T cells (DETC), into IL-7Rα-deficient mice, and we found that they partly rescued γδ T cells in the adult thymus but not in the spleen. Introduction of an additional Bcl-2 transgene had a minimal effect on γδ T cells in the adult thymus of these mice. In contrast to the adult thymus, the introduction of the Vγ3/Vδ1 TCR transgene into IL-7Rα−/− mice completely restored Vγ3+ T cells in the fetal thymus and DETC in the adult skin. On the contrary, the same Vγ3/Vδ1 TCR transgene failed to rescue DETC in the skin of IL-2Rβ-deficient mice, even with the additional Bcl-2 transgene. These results suggest ...
Memory regulatory T cells reside in human skin
Journal of Clinical Investigation, 2014
Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.