REGULATION OF RECEPTORS ON T-LYMPHOCYTES

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Changes that take place during cell differentiation often involve the activation and repression of specific genes. The common origin of B and T lymphocytes suggests the possibility of overlap in the transcriptional regulation of their genes, particularly those expressed soon after divergence of the two lineages. This idea is supported by the observation that the immunoglobulin mu heavy chain gene is active in some T cells whereas the later activated kappa light chain gene is not. Thus, comparison of the transcriptional regulation of early B and T cell genes (and the factors that control them) may to provide insights into the signals initiating lymphocyte. The T cell receptor (TCR) beta chain gene and the interleukin-2 receptor alpha chain gene (IL-2Ralpha) are both expressed early in the course of T cell ontogeny. Experiments outlined in this proposal seek to identify the cis-acting sequence elements (by transfection assays and analysis of transgenic mice) and the corresponding trans-acting factors that specify the developmentally correct activation of the TCR genes. This will allow future studies on the regulation of the factors themselves, presumably in response to environmental cues. IL-2Ralpha is further inducible upon T cell activation and recent reports suggest that this might be true of the TRC genes as well. IL-2Ralpha gene induction is dependent upon a sequence motif that binds the inducible factor NF-KB. Curiously, a similar motif is located in the TCR locus as well, suggesting that both genes may be regulated by the same factor. Transfections into B and T cell lines is expected to not only clarify the functional role of this site but to also reveal other regulatory circuits that prevent constitutive expression of these genes in B cells where NR-KB is constituitively present.