Costimulatory molecules have been demonstrated to play a central role in the regulation of T cell activation. Triggering of the T cell receptor (TCR)/CD3 complex in the absence of a costimulatory ligand is insufficient to induce T cell activation and under certain conditions lead to peripheral T cell tolerance (anergy). The importance of the B7 costimulatory pathway for tolerance has been inferred largely from in vitro studies; however, recent in vivo studies indicate that B7 antagonists can significantly prolong graft survival and suppress T cell dependent antibody responses in vivo. These findings give impetus to examining the role of B7 in the induction of anergy in vivo. The major objective of this project is to examine the role of the B7 costimulatory pathway in the induction of anergy in vivo, using mice with genetically dysregulated B7 expression. Such an approach is essential for defining the role of B7 in physiologic, antigen-specific immune responses and for designing rational therapeutic approaches involving manipulation of costimulatory signals.
The specific aims are: 1. To determine whether elimination of blocking of the B7 costimulatory signal induces tolerance in naive T cells in vivo The role of B7 in T cell activation will be analyzed in B7 deficient mice, generated by homologous recombination and embryonic stem cell technologies, and by treating mice with specific B7 antagonists. The consequences of TCR triggering in the absence of B7 will be explored mechanistically. The relationship of hyporesponsiveness, anergy and apoptosis will be examined. 2. To analyze the immune system of mice which constitutively express B7 The development and analysis of transgenic mice overexpressing B7 complements the in vivo study of the effects of B7 elimination or antagonism. B7 expression is normally tightly regulated such that is expressed on APCs only after cell activation. Overexpression of B7 may block tolerance and lead to systemic autoimmunity. These studies will critically test the importance of regulated B7 expression in vivo. 3. To analyze the development and function of T cell receptor transgenic T cells in B7 deficient and B7 overexpressor transgenic mice. Interbreeding the TCR transgene into B7 deficient and B7 overexpressor transgenic mice will enable a quantitative study of the effects of B7 dysregulation on the development and activation of antigen-specific T cells. The fates of anergized T cells and primary T cell responses will be examined. Thus, this project emphasizes a major theme of the Program, namely mechanisms and functional consequences of costimulation in vivo using genetic methods of alter expression of costimulators in mice.
Showing the most recent 10 out of 117 publications
