We will study the regulation of rearrangement and expression of murine T- cell antigen receptor and gamma chain genes. Normal fetal tissues, hybridomas we have prepared from mouse fetal thymocytes, and cells and tissues from transgenic mice carrying a rearranged beta or gamma gene will be analyzed for alpha, beta and gamma gene rearrangement and expression. We will also attempt to develop a hybridoma that can carry out some of these rearrangements in vivo. The results will show whether there is an order in the rearrangement of genes in these three unlinked gene families, and whether the presence of a rearranged gene in a transgenic mouse has effects on further gene rearrangements. It will therefore be possible to determine whether feedback models, proposed to regulate immunoglobulin gene expression, also apply to genes that rearrange in T cells. We will also determine if in ontogeny there is an order in the expression of V gene segments within a gene family. If ordered rearrangement in the 3 gene families or ordered V gene expression can be demonstrated, then this will permit a better classification of the maturity of T cells with different cell-surface phenotypes. This will aid our understanding of the thymic differentiation process, and may permit a better classification of T cell malignancies. We will also test whether strains of mice prone to autoimmune disease display any abnormalities in the developmental program of T cell receptor V gene expression. In the transgenic mice, the tissue-specific control of gene expression can be assayed independent of the control of gene rearrangement, and by correlating expression of the introduced beta or gamma gene with the expression of Lyt-2 and L3T4, the relationship between the type of MHC molecule recognized and the expression of these genes can be indirectly studied. The effect of expression of different MHC haplotypes on the expression of the transgene will also be analyzed. These studies will give us insight into the function, as well as the regulation of rearrangement and expression of beta and gamma genes.
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