Cytokines, through their ability to regulate cellular proliferation and differentiation, are important for the generation of an effective immune response. The CD4+ (helper) population of T lymphocytes (TR cells) can be subdivided, based on the cytokines they secrete, into TRI (IL-2 and IFN- gamma) and TH2 (IL-4, IL-5, and IL-10) subsets. The cell mediated immune responses that are observed in organ specific autoimmune diseases [e.g. experimental allergic encephalitis (EAE) and diabetes mellitus] suggest that TRI cells may be important for the pathogenesis of these diseases. In addition, transfer experiments with TRI cells have shown that they are important for the generation of EAE in mice. Interestingly, TH2 cells have been shown to prevent the TH1 mediated pathology seen in this disease. This suggests that the cytokines produced during the immune response associated with this disease can determine the clinical manifestation of the disease process. IFN-gamma can modulate both the development and growth of TH cells. Interestingly, IFN-gamma can inhibit the proliferation of TH2, but not that of TH1 cells. This suggests that TH subsets might differ in their activation of the IFN-gamma signaling pathway. Examination of the IFN- gamma signaling in TH cells reveals that TH1 cells are unable to activate the transcription factor STF-IFNgamma in response to IFN-gamma. We find that the inability to induce STF-IFNgamma in TR1 cells is due to the absence of the beta chain of the IFN-gamma receptor (termed AF-1). These data indicate that TH1 cells utilize a novel mechanism to achieve an IFN- gamma resistant state. Because naive TH cells lose IFN-gamma responsiveness as they differentiate into TH1 cells we have hypothesized that the regulation of AF-1 might play a role in the differentiation of naive TH cells into TH1 cells. To test this theory, we have produced transgenic mice that overexpress AF-1 in T cells. Preliminary results demonstrate that the T cells from these mice do not differentiate into TH1 cells in response to IFN-gamma. We propose to use mice that overexpress AF-1 to study the role of this protein in the differentiation of CD-4+ and CD8+ cells. These transgenes will be crossed into a generic background in which EAE can be induced and these mice used to determine the role of IFN- gamma signaling and different T cell subsets in the generation of this autoimmune disease.
