T lymphocytes undergo two selection processes during development in the thymus: tolerance and positive selection. This grant proposes to study these developmental events by using transgenic mice which express T cell antigen receptors. To a large extent, the transgene encoded receptor replaces endogenously encoded receptors in these animals, allowing one to study development in a large population of T cells with identical specificity. The murine T cell response to pigeon cytochrome c and class II major histocompatibility complex encoded (MHC) molecules will be used as a model system. Experiments will address how the structure of the T cell antigen receptor influences the recognition of MHC molecules during T cell maturation in the thymus. Two separate lines of transgenic animals which express antigen receptors that differ by only a single amino acid will be analyzed. This single amino acid difference results in a change in the pattern of MHC restriction in vitro. Whether this region of the T cell antigen receptor also alters the fine specificity of MHC recognition during positive selection in the thymus will be determined by analyzing the development of T cells in transgenic mice of varied MHC haplotypes. Transgenic mice which express these T cell antigen receptors will also be used to study the mechanisms of tolerance to self-antigens. Two approaches will be used. First, neonatal transgenic mice will be rendered tolerant to pigeon cytochrome c by repeated injection of the antigen. The maturation of T cells in these animals will be analyzed in order to determine the mechanism of tolerance to this soluble antigen. Second, gene constructs encoding a secreted or cytoplasmic form of a fragment of pigeon cytochrome c will be expressed in vitro and in transgenic mice. These experiments will address how the cellular localization of a self-antigen influences its ability to induce tolerance in class II MHC restricted T cells. Double transgenic mice which express a T cell antigen receptor and its specific antigen will also be produced. These mice will allow a careful analysis of the mechanism of tolerance induction to the transgene encoded antigens. The issues concerning T cell development that are addressed by this proposal relate to how a mature T cell repertoire is selected, both by elimination of auto-destructive specificities and by positive selection for self recognition. Certainly these developmental events are central to understanding many facets of autoimmune disease and MHC linked disease susceptibility.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Experimental Immunology Study Section (EI)
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Scripps Research Institute
La Jolla
United States
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