title: 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)-gamma 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-gamma-(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-gamma, but not IL-4 in response to T cell receptor-mediated stimulation. Use of neutralizing anti-IFN-gamma antibody indicated that IL-12 not only directly promoted Th1 development but also indirectly inhibited Th2 development through stimulation of IFN-gamma 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.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, OH 44195, USA. diiulin@cesmtp.ccf.org
authors.forename: N A
authors.initials: NA
authors.lastname: DiIulio
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: R L
authors.initials: RL
authors.lastname: Fairchild
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology*; D005260:Female; D006241:Haptens / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D006241:Haptens; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma