Biochemical Studies of Human Cell Surface Markers

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

T lymphocytes mature in the thymus, where they undergo a series of differentiation, expansion and selection events under the influence of the thymic environment. The main objective of this proposal is to study regulation of expression of the CD3gamma, delta and epsilon genes. The CD3 genes are involved in intrathymic differentiation from the pre-TCR phase on and perhaps earlier. Thus, CD3gamma, delta and epsilon are of paramount importance in positive and negative selection processes. At later stages of T lymphocyte development, the CD3 proteins control surface expression of the TCR/CD3 complex and are indispensable for antigen/MHC driven signal transduction. Previously, we had shown that the CD3gamma, delta and epsilon genes map closely together in a small cluster on human chromosome 11q23 (mouse chromosome 9). CD3 gamma and delta are transcribed divergently, their transcription start sites being 1.2 to 1.4 kb apart. The CD3epsilon gene is located 26 kb downstream from the CD3delta gene and is transcribed in the direction of the CD3gamma gene. Although the CD3gamma, delta and epsilon genes are primarily expressed in thymus derived lymphocytes, CD3epsilon has been found in human and murine activated natural killer cells. In spite of the similarities in tissue distribution and the clustering of these three genes, our studies have clearly demonstrated that their respective regulatory elements are distinct. Our interest in the CD3gamma, delta, epsilon genes cluster lies therefore not only in the important functions of their gene products, but also in the unique developmental regulation of their expression. Our first hypothesis is that expression of CD3gamma, delta and epsilon is governed by unique T cell specific mechanisms in addition to common elements. A second hypothesis is that induction of CD3gamma, delta or epsilon in the precursor T cell utilizes distinct pathways. We specifically propose to: 1 Study T cell specific transcriptional regulation of the CD3delta gene; 2 Investigate the molecular mechanisms that govern expression of the CD3epsilon gene in T and NK cell; 3 Characterize transcriptional elements involved in T cell specific expression of the CD3gamma gene; 4 Examine the regulation of the CD3gamma, delta and epsilon genes during early lymphocyte development.