Resident Skin-specific γδ T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation (original) (raw)
Related papers
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.
Journal of Allergy and Clinical Immunology, 2001
Methods: Mice with targeted gene deletions were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. Results: RAG2 -/mice, which lack both T and B cells, did not exhibit cellular infiltration, induction of dermal IL-4 mRNA, or elevation of serum IgE after OVA sensitization; all of these features were present in B-cell-deficient IgH -/mice. T-cell receptor α -/mice did not display cellular infiltration, IL-4 mRNA expression, or increased IgE levels after OVA sensitization, but these responses were elicited in T-cell receptor δ -/mice after sensitization. Absence of CD40 had no effect on these responses. Conclusion: These results suggest that αβ T cells, but not γδ T cells, B cells, or CD40L-CD40 interactions, are critical for skin inflammation and the T H 2 response in AD. (J Allergy Clin Immunol 2001;107:359-66.)
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.
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 ...
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.
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.
Journal of Investigative …, 2007
The purpose of this study is to identify invariant natural killer T cells (NKT cells) in cellular infiltrate of human allergic contact dermatitis (ACD) skin challenge sites. Skin biopsy specimens were taken from positive patch test reactions from 10 different patients (9 different allergens) and studied by immunochemistry, real-time PCR, nested PCR, and in situ hybridization to identify NKT cells and the cytokines associated with this cell type. Invariant NKT cells were identified in all the 10 skin biopsy specimens studied, ranging from 1.72 to 33% of the cellular infiltrate. These NKT cells were activated in all cases, as they expressed cytokine transcripts for IFN-γ and IL-4. Invariant NKT cells are present in ACD, regardless of the allergen that triggers the reaction, and are in an activated state. We conclude that innate immunity plays a role in late phases of type IV hypersensitivity reactions and may be responding to self-lipids released during allergic inflammation. These data complement the previous work by other investigators that suggest that NKT cells are important in the early cellular response during primary immune responses to allergens. Herein, it is demonstrated that NKT cells are constantly present during the late elicitation phase of human type IV hypersensitivity reactions.
Clinical and Experimental Immunology, 1991
SUMMARY The biological role of T cell receptor (TCR) γδ bearing cells is currently not fully understood. Recently, a monoclonal antibody (TCRδ1) reacting against the whole molecule became available which facilitates the direct analysis of TCR-γδ+ cells. We studied 11 children with atopic dermatitis, 20 children with atopic asthma, 18 adults with atopic dermatitis and 38 healthy age matched controls aged 4–51 years. Lymphocytes were isolated from heparinized peripheral blood and the proportion of TCR-γδ+ lymphocytes was determined by FACS analysis. Patients with atopic diseases yielded a significantly (P<0.01) lower proportion of TCR-γδ+ cells compared with normal controls (median 4.8%versus 7.1%). The percentage of TCR-γδ+ cells showed an age-dependent decline in both the patient group (r=—0.49, P<0.01) and the control group (r=–-0.40, P<0.01). In addition, the proportion of cells which expressed CD8, TCR-γδ or CD4, TCR-γδ simultaneously was determined by double labelling i...
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.