CD4+ T cells, activated in response to antigens presented by MHC class II molecules, differentiate from a common, naive precursor into Th1 or Th2 subtypes. These subtypes are distinguished by the cytokines they produce. Th1 cells make interferon gamma and IL-2, while Th2 cells make IL-4, IL-5 and IL-6. At least three mechanisms determine Th subset bias during immune response. The most widely studies mechanism involves conditions present during initial antigen stimulation and differentiation of the Th0 cell precursor. Thus, Th0 cell activation in the presence of IL-12, IFNgamma, low antigen load, and possibly specific accessory molecules such as B7-1, results in preferential differentiation of Th0 cells to the Th1 phenotype. Once differentiated, Th1 cells are more susceptible to antigen driven activation induced cell death (AICD) than Th2 cells. Th1 cell populations may be more susceptible to AICD because these cells may undergo a form of autocrine cell death. AICD might lead to ultimate dominance of Th2 cells subsequent to antigenic stimuli unless there is a counterbalancing mechanism for selective elimination of Th2 cells. Using a murine model of coxsackievirus B3 (CVB3)-induced myocarditis, we have uniquely shown that T cells expressing the gamma-delta T cell receptor selectively kill differentiated Th2 cells but spare Th1 cells. Our studies indicate that expression of MHC class II IE molecules is necessary for gammadelta+ T cell regulation of Th2 cell response. These molecules may positively select unique populations of gammadelta+ T cells (Vgamma/Vdelta) during T cell ontogeny. Alternatively, gammadelta+ T cells capable of killing Th2 cells may require interaction with IE for activation or target cell recognition. The purpose of this application is to establish a link between the presence of IE and the activation of gammadelta T cells that regulate cytokine bias by death of Th2 cells. We propose that a specific type of gammadelta T cell dominating in IE+ mice kills Th2 cells leaving a Th1 dominant response. The following specific aims will test this model: 1) To determine if unique gammadelta subsets promote Th1 cell responses; 2) To determine how IE influences gammadelta T cell dependent death of Th2 cells and consequent Th1 bias; and 3) To determine the mechanism of gammadelta T cell dependent Th2 cell death.
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