The overall goal of this project is to examine mechanisms of T and B lymphocyte tolerance and the failure of tolerance (autoimmunity) as well as the function and regulation of T and B lymphocyte surface receptors involved in these immune phenomena. These studies will make extensive use of transgenic mice and state-of-the-art cell sorting capabilities, as well as the newly developed technique of gene targeting and novel approaches to gene regulation. Two studies will investigate the mechanisms of T cell tolerance, including both thymic deletion and T cell anergy, in transgenic mice expressing distinct T cell receptors, each with potential autoreactivity. In parallel, mechanisms of B cell tolerance will be examined in transgenic mice expressing an autoantigen with distinct tissue distributions or subcellular localizations. The role of a peripheral lymph node homing receptor in the lymphadenopathy characteristic of the autoimmune g/d mouse will be investigated. The influence of the MHC haplotype on the T cell repertoire for an autoantigen (myelin basic protein) capable of inducing an autoimmune disease (experimental allergic encephalomyelitis) will be examined in different mouse strains as well as through the use of T cell receptor and class II MHC transgenic mice. The role of the invariant chain (Ii) in class II MHC expression and function will be approached both in transgenic mice and by the use of targeted recombination to generate mutant mice that lack Ii expression. Gene targeting will also be used to examine the biological role of a gene encoding a serine esterase expressed by cytotoxic T cells. Cytotoxic T cell development will also be examined in studies on the regulation of expression of CD8 and the mechanisms controlling the choice between CD8 and CD4 expression during thymocyte differentiation. New vectors and methodologies for gene regulation studies will also be developed with the use of the fluorescence-activated cell sorter (FACS) as a detection system. Finally, the interaction of antibody and antigen will be studied using mutants selected on the FACS.
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