BIOCHEMICAL STUDIES OF HUMAN T CELL SURFACE MARKERS

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Differentiation of eukaryotic cells involves precisely orchestrated changes in transcription and translation of several sets of genes. The final stages of differentiation of T lymphocytes occur primarily within the thymus gland. The T3/T cell receptor complex, consisting of a variable heterodimer of the T cell receptor (Alpha and Beta chains) and the three invariable polypeptides (T3-Gamma, Delta and Epsilon), is expressed only on the surface of mature thymocytes. This complex is indispensable for the interactions between T cells and antigen presenting cells or target cells and plays a major role in the initiation of T cell activation. To explore the nature of assembly of the T3/T cell receptor complex during T lymphocyte maturation we will isolate the genes coding for the three invariable polypeptide chains (T3-Gamma, Delta and Epsilon) of the T3/T cell receptor complex in humans and mice. Thymocyte subpopulations and T leukemic cells will be analyzed for expression of the T3 genes in relation to the expression of the T cell receptor Alpha and Beta genes and the T lineage specific genes T4 and TBeta. The assemblage of the T3/T cell receptor complex will be investigated using several approaches including the generation of somatic cell variants. In vitro DNA transfer techniques and site directed mutagenesis. The regulation of expression of the genes of the T3/T cell receptor complex will be studied by a series of in vitro experiments. These include the search for tissue specific transcriptional enhancer elements. The factors that determine the developmental regulation of the T3/T cell receptor complex will be studied in vivo by generating transgenic mice using mouse/human hybrid T3-Gamma, Delta and Epsilon genes. The proposed experiments with transgenic mice will lead to an understanding of the coordination of transcriptional and translational control of T lineage specific genes. The data obtained from these studies will also contribute to our knowledge of leukemogenesis and other disease states such as immunodeficiencies.