REGULATION OF THE T CELL-SPECIFIC GENE CD7

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Hematopoietic differentiation involves the interaction of genetic events within the cell and biochemical signals in the microenvironment. T lymphocytes derive from multipotent hematopoietic stem cells which migrate from the fetal liver and bone marrow to the thymus. Within the thymus, T cell ontogeny is marked by the sequential appearance of many lineage specific molecules. While the temporal expression of these molecules has been well studied, the molecular mechanisms responsible for the coordinated activation and expression of the genes for these developmental and tissue specific proteins are largely unknown. The human CD7 molecule is one of the earliest markers of the T cell lineage, appearing on multipotent hematopoietic precursors in the fetal liver and bone marrow prior to their migration to the thymus. CD7 continues to be expressed throughout T cell development and is found on 85% of peripheral T cells. The overall goal of these studies is to understand T cell development through the study of the T cell specific gene, CD7. Since CD7 is one of the earliest T lineage specific genes expressed, the activation of this gene may help convey T cell specificity to hematopoietic stem cells. We propose to identify and characterize the cis-acting elements which are responsible for the tissue specific expression of the CD7 gene using both in vivo and in vitro systems. In addition, we will study the possible extinction of CD7 gene expression by negative regulatory elements located upstream of the gene and explore the consequences of retroviral infection on the regulation of the gene. We believe that understanding the transcriptional regulation of the CD7 gene will yield significant knowledge about mechanisms of tissue specificity and the early molecular events associated with T cell lineage determination. Because of the central role of the T cell in modulating the immune response, an understanding of the relationship between normal and abnormal T cell development is crucial to understanding the pathogenesis and etiology of autoimmunity.