The goal of this project is to broaden our understanding of the physiology and regulation of early events in T cell activation. Lymphocyte metabolism and effector function expression are regulated by antigen/mitogen and lymphokine binding to cell surface receptors. We are investigating the consequences of mitogen mediated signals by isolating and characterizing genes which are transcriptionally regulated by these events. We have constructed a subtracted cDNA library enriched for genes that are transcriptionally induced within four hours after stimulating peripheral blood T cells with PHA and PMA. Utilizing the library in combination with labelled subtracted probes (activated T cells cDNA minus resting T cell mRNA), we have isolated over 60 novel cDNA clones which represent the immediate response of resting human peripheral blood T cells when activated by mitogen to proliferate. This primary response is highly complex, both in terms of the number of inducible genes as well as the diversity of their regulation. Although a majority of the genes involved are shared with the activation response in normal human fibroblasts, a significant number are more restricted in their tissue specificity and thus may be encoding or effecting the differentiated functions of activated T cells. Surprisingly many inducible genes are inhibited by the immunosuppressive drug cyclosporin A, which is known to repress the transcription of several lymphokine genes. In addition, a subset of inducible genes are stimulated to con- stitutive expression in T cell clones infected with the immortalizing human retrovirus, HTLV I. Such abnormally-expressed genes may play a role in the deregulated growth of such cells.
