The cytotoxic thymus derived lymphocyte (CTL) is a critical element in the effector phase of the immune response. It plays a central role in the destruction of virus-infected cells and in the rejection of foreign tissue grafts or tumors. Moreover, CTL's might also be involved in the pathogenesis of some autoimmune diseases. The main objective of this proposal is to study the target antigen recognition and the initial phase of signal transduction by T cell receptors. The intention of the proposed studies is to unravel the complexity of the T cell receptor/T3 complex on the surface of CTL, its biosynthesis and the possible molecular mechanisms of transmembrane signalling after ligand/receptor interaction has been established. In addition to a description of human T cell receptors specific for HLA-A2 and -B7 antigens, T cell receptor function of murine CTL will be studied. This system offers a number of unique advantages: 1) availability of well defined human and murine cytotoxic T cell clones and target cells. 2) assays by which receptor/antigen interactions can be studied are used routinely. 3) considerable information about the protein structure of the T cell receptor/T3 complex on human and murine T cells has been collected. 4) expertise in recombinant DNA technology has been introduced in our laboratory.
The specific aims of the proposed project include: a) the study of the B and a-chains of the T cell receptor on the surface of human CTL's, b) the study of the role of the components of the T cell receptor/T3 complex in the early stages of cytolysis, c) investigation of the role of a2-microglobulin and the acessory structures T8 (Lyt2) and LFA-1 in recognition of class I MHC antigens by CTL, d) a detailed description of the components of the human and murine T cell receptor/T3 complex and its biosynthesis and, e) examination of the mode of signal transduction by the T cell receptor/T3 complex.
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