Diversion of CD4+ T cell development from regulatory T helper to effector T helper cells alters the contact hypersensitivity response

Abstract

Cutaneous sensitization to reactive haptens and subsequent challenge results in a T cell‐mediated response, contact hypersensitivity (CHS). Recent results from this laboratory have indicated that hapten sensitization induces two populations of reactive T cells: CD8⁺ T cells producing interferon (IFN)‐γ which mediate the response and CD4⁺ T cells producing interleukin (IL)‐4 and IL‐10 which negatively regulate the magnitude and duration of the response. Since CD4⁺ T cell development to either IFN‐γ‐ (Th1) or IL‐4/IL‐10‐ (Th2)‐producing cells is dependent upon the cytokine environment during antigen priming, we hypothesized that CD4⁺ T cell induction in a Th1‐promoting environment would not only alter the CD4⁺ T cell cytokine‐producing phenotype but also the course of the CHS response. Administration of the Th1‐promoting cytokine IL‐12 during hapten sensitization resulted in a CHS response of greater magnitude following challenge and extended the duration of the response. In hapten‐sensitized mice depleted of CD8⁺ T cells, treatment with IL‐12 induced effector CD4⁺ T cells. Histological examination of challenged ear tissue from these mice indicated minimal edema and an acute mononuclear cell infiltration more typical of classical delayed‐type hypersensitivity than CHS. Hapten‐primed CD4⁺ T cells from IL‐12 treated, sensitized mice produced IFN‐γ, but not IL‐4 in response to T cell receptor‐mediated stimulation. Use of neutralizing anti‐IFN‐γ antibody indicated that IL‐12 not only directly promoted Th1 development but also indirectly inhibited Th2 development through stimulation of IFN‐γ production at the time of hapten sensitization. Overall, these results demonstrate that diversion of CD4⁺ T cell development to Th1 effector cells rather than to Th2 cells alters the efferent nature of CHS and removes a primary regulatory mechanism of the immune response.