The hallmark of the immune system is the remarkable ability to discriminate between self and foreign proteins displayed as peptides bound to self-major histocompatibility complex (MHC) molecules. T lymphocytes acquire this ability during development in the thymus in which low avidity interactions between T-cell receptors (TCRs) and self-MCH/peptide result in positive selection. High avidity interactions in the thymus result in negative selection and deletion of potentially autoreactive T-cell repertoire that is self-tolerant and self-MHC restricted. TCR affinity, MHC/peptide density and co-receptor engagement contribute to the overall avidity of the interaction between T-cells and antigen presenting cell (APC). This avidity sets up a balance between positive and negative selection and establishes the activation requirements of peripheral T-cells. The overall goal of this application is to correlate the thymic selection environment with the functional phenotype of the peripheral CD8T cell repertoire. Specificity of peripheral CD8 T-cells. To do this they will alter class I expression or CD8 interaction during thymic development and determine how it affects the ability of peripheral CD8 T-cells to distinguish APC expressing different levels of class I/peptide complexes. To address these questions, unique MHC Class I transgenic mice that express a single class I allele will be engineered. Using these mice, the diversity of the CD8 T-cell repertoire selected by a single class I allele, in the absence of other class I molecules, will be characterized. These analyses will probe mechanisms of tolerance to self-antigens and avoidance of autoimmune responses. Furthermore these studies will determine factors influencing activation requirements of self-restricted responses to tumor antigens and infectious virus as well as how individual MHC alleles contribute to alloreactive responses and transplantation tolerance.
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