complete activation of T lymphocytes requires, in addition to stimulation via the TCR/CD3 complex, participation of one or more costimulator molecules. For Th1 cells, ligation of the TCR complex in the absence of costimulation results in anergy, a state characterized by deficient IL-2 production and proliferation. One costimulator molecule for IL-2-producing T cells is CD28, which interacts with the ligands B7-1 and B7-2 expressed on antigen-presenting cells and other cell type. CTLA4 is a homologous molecule expressed on activated T cells that also binds to B7-1 and B7-2 but which may have a negative function for T cell activation. In contrast to Th1 cells, less is known about the costimulatory requirements of IL-4 producing Th2 cells. The principal goals of this Project are to characterize the signaling defects in anergic Th1 clones that correlate with the anergic state, to determine if the observed changes are causally related to an inability to produce IL-2, to identify the normal signaling pathway(s) that mediate the functions of CD28, to analyze the biochemical consequences of CTLA4 ligation on the functions of Th1 and Th2 cells, and to identify and characterize the costimulator molecule(s) for Th2 cells . These studies will take advantage of a panel of well- defined Th1 and Th2 clones generated in our laboratory, as well as a series of transgenic and knockout mice. The focus will be on positive and negative regulation of the signaling studies will be aided by a panel of tumor cell transfectants that express permutations of I-Ad, B7-1, B7-2, and ICAM-1. Inasmuch as cytokine production and proliferation by established Th2 clones are unaffected by CD28/B7 blockage, additional cistimulator molecules that regulate the growth of Th2 cells will be identified and characterized. Once identified, the signaling pathways triggered by these ligands will be contrasted with those induced by CD28 and IL-1. Collectively, these studies should provide a more thorough understanding of the function of cistimulator receptors and their biochemical signals in the control of T cell activation versus inactivation, and in the regulation of distinct T cell subsets. Such information should have broad implications for transplantation, autoimmunity, and the immune response against cancers.
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