The vast majority of TCR gamma delta+, CD4-, CD8- T cells resident in the adult mouse epidermis expresses tissue-specific V-region genes (V gamma 3/V delta 1) in the absence of junctional diversity. The role this unique T cell population plays in the immune surveillance of the skin is not clear. It has been shown that dendritic epidermal T cells (DETC) were activated by stressed keratinocytes and that stimulated DETC produced, for example, a keratinocyte-specific growth factor. To investigate whether DETC are involved in the induction of a contact allergy, we examined the influence of contact sensitizers and nonsensitizing contact irritants on the DETC response toward epidermal symbionts. We show that 9 of 15 cloned DETC are specifically activated, apparently in a non-MHC-restricted way, to proliferate in the presence of keratinocytes or unseparated epidermal cells, which were treated with a sensitizing agent either in vivo or in vitro. All seven tested contact sensitizing substances activated all of the reactive DETC, while keratinocytes/epidermal cells treated with nonsensitizing irritants were as nonstimulatory as vehicle controls. We demonstrate that direct cell to cell contact of DETC and stimulatory keratinocytes/epidermal cells was required and that the TCR was involved in the induction of DETC proliferation. This specific reactivity of DETC toward keratinocytes or epidermal cells pretreated with a contact sensitizer may be indicative of participation of epidermal T cells in the induction of a contact sensitivity and points to a possible role of DETC in the skin immune system.