T lymphocytes play a key role in the immune response to a wide variety of infectious and neoplastic pathogens. T cell antigen recognition is mediated by a heterodimeric alpha/beta T cell receptor molecule which recognizes antigenic peptides bound to major histocompatibility antigens on the surface of antigen-presenting cells. Although the expression of the TCR alpha and beta genes is T cell specific of developmentally regulated during T cell ontogeny, relatively little is understood about the molecular mechanisms which regulate TCR alpha and beta gene expression during T cell differentiation. We have recently identified potent transcriptional enhancer elements which are located 3' of both the human TCR alpha and beat genes and which are required for TCR alpha and beta gene transcription in T cells. The activity of the TCR alpha enhancer is T cell-specific (and moreover appears to be restricted to TCR alpha/beta cells) while the TCR beta enhancer displays lymphoid-specific activity ie. it is active in both T and B cells. In addition the two enhancers are controlled by the binding of distinct sets of novel trans-acting nuclear transcriptional regulatory proteins which differ from those which have previously been reported to regulate the expression of immunoglobulin genes. Finally we have shown that in addition to a potent transcriptional enhancer, the 3' flanking sequences of the human TCR beta locus contain one or more negative transcriptional regulatory elements (silencers) which are active in both B and T cells. The studies described in this proposal are designed to elucidate the molecular mechanisms which regulate TCR alpha and beta gene transcription. Specifically we propose to precisely identify the cis- acting sequences and trans-acting factors which activate the TCR enhancers, and to study the development. In addition we will address the role of the TCR beta promoters in determining the T cell-specific expression of the TCR beta genes and attempt to elucidate the molecular mechanisms responsible for the transcriptional silencer activity which we have observed in the TCR beta locus. The proposed studies are relevant to both normal T cell development and to the molecular pathogenesis of certain T lymphoblastoid tumors which have been shown to display chromosomal translocations into the human TCR alpha locus on chromosome 14.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Allergy and Immunology Study Section (ALY)
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University of Michigan Ann Arbor
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Ann Arbor
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