Contact sensitivity has served as a useful model for the primary activation of T cells in skin and skin-associated lymphoid tissue. We have been interested in the early signals necessary for the induction of an allergen-specific T-cell response, as well as the factors controlling the intensity and extent of such an immune reaction. Because cytokines qualified as possible candidate molecules involved in directing primary immune responses in skin, we studied the early changes in the cytokine pattern of the epidermis. Apart from defining a cytokine pattern specifically induced only after application of allergen, we also identified Langerhans-cell-derived interleukin (IL)-1 beta as the first cytokine to be induced by allergen, within 15 min of hapten application. Further experiments demonstrated that IL-1 beta also subserved an essential function for the induction of contact sensitivity reactions, as injection of IL-1 beta into the ears of mice mimicked the application of contact allergen on the morphologic, phenotypic, and functional level. In addition, injection of anti-IL-1 beta monoclonal antibody before application of allergen completely prevented sensitization. We also identified the production of IL-10 by murine keratinocytes. IL-10 may serve as a counterregulatory molecule in contact hypersensitivity, as it functionally suppressed Langerhans cell accessory cell function by preventing the expression of certain costimulatory molecules on the surface of these antigen-presenting cells. Indeed, IL-10 converts those cells from potent inducers of primary immune responses to tolerizing antigen-presenting cells. The tolerizing function of IL-10 has also been described in vivo. Intradermal injection of IL-10 before application of the allergen induces hapten-specific tolerance in vivo. In aggregate, our data indicate that epidermally derived cytokines are intimately involved in the modulation of immune reactions in skin, in some cases enhancing sensitization and in others inducing specific immunologic tolerance and anergy.