While pathogenic T cells have been identified for several diseases with epithelial cell damage, an autoimmune T cell-mediated response targeted against a known keratinocyte antigen has not been reported. Previously we described an autoimmune response directed to the mouse epidermal cell antigens, Skn. For our murine model, primed Skn-immune lymphocytes are adoptively transferred to recipients, which develop lesions at the site of mild skin trauma. In this study we investigated the nature of the autoimmune component of the Skn response. A time-course study demonstrated a relationship between the number of primed Sknimmune cells injected and the severity of skin lesions in the recipients. Immunohistochemical staining revealed the presence of both CD4+ and CD8+ T cells in lesional skin, with a predominance of CD4+ T cells. To support a role for CD4+ T cells in the initiation of the autoimmune response, Skn-immune donor cells were either enriched or depleted of various subsets prior to transfer into recipients, which showed that CD4+, but not CD8+, T cells were essential for induction of lesions. Analysis of mRNA for T-helper (Th) cell cytokines in lesional skin displayed a Th1 bias, and treatment with cyclosporin A (CsA) or anti-interleukin (IL)-2 antibody controlled the development of lesions. Overall the results clearly show an immunopathogenic profile consistent with a T cell-mediated mechanism.