The proposed studies will address the role of major histocompatibility complex (MHC) products in the selection of murine T lymphocytes within the thymus. Some of the studies will involve analysis of the role of thymic epithelial cells and hematopoietic cells in positive and negative selection of T cells. These studies will involve analysis of T cells expressing T cell receptor (TCR) Vbeta regions previously shown to be subject to MHC- dependent positive and negative selection. The same issues will be explored by analyzing mice deficient for expression of Beta2-microglobulin (hence MHC Class 1) molecules, produced by homologous recombination. The status of selection will be determined at various stages in ontogeny and in subtypes of immature thymocytes, in order to stage the selection processes. In addition, specific experiments will address three models of positive thymic selection, using transgenic mice expressing mutant class I MHC genes or constitutive CD4 genes. The regions of TCR chains and MHC molecules involved in TCR-MHC recognition during positive selection will be investigated by sequence-analysis of TCR cDNAs isolated by the PCR reaction, and analysis of MHC mutant mice, respectively. Finally the effects of the M1s locus on selection of T cells expressing Vbeta14 will be studied, in the hope of learning more about the role of M1s in T cell immunobiology. The proposed studies are all addressed at understanding the regulation of T cell development. A basic understanding of T cell development is necessary to understand the genesis of genetic and infectious immune deficiencies, including AIDS.
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