This proposal describes experiments to explore the role of the CD4 and CD8 co-receptors in T cell development, with particular focus on the intracellular functions of CD4 and CD8 and how they influence T cell fate. We have shown that a hybrid co-receptor consisting of the extracellular portion of CD8 and the cytoplasmic portion of CD4 leads to the appearance of large numbers of class I specific CD4+ T cells, implying that CD4 intracellular signals favor the development of CD4 lineage T cells. We now propose to pin-point the region of the CD4 cytoplasmic domain that is responsible for this effect by mutagenizing the CD8/CD4 hybrid co-receptor and analyzing the mutants in cell lines and in mice. Because the CD4 cytoplasmic domain interacts with the tyrosine kinase, Lck, we will particularly focus on testing the role of Lck in generating CD4 cells. We also propose to investigate whether CD4 intracellular signals act before or after lineage commitment by a kinetic analysis of thymic selection. Finally, we will explore in more detail the role of the cytoplasmic domain of CD8 beta by a biochemical and cellular analysis of mice whose CD8 beta lacks a cytoplasmic domain. These experiments will lead to a better understanding of the workings of the mammalian immune system, which in turn should improve our understanding of defects in the immune system, such as immunodeficiency, auto-immunity, and leukemia, and may also provide a basis for manipulating the immune system to improve our resistance to cancer or other diseases.
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