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.