Resident Skin-specific γδ T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation

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 dermatitis in FVB.δ(−/−) mice were down-regulated by Vγ5(+) DETC, but not by epidermal T cells expressing other γδ TCRs. This study demonstrates that functional impairment at an epithelial interface can be specifically attributed to absence of the local TCR-γδ(+) IEL subset and suggests that systemic inflammatory reactions may more generally be subject to substantial regulation by local IELs.