The normal development and activation of T lymphocytes are required both to ensure appropriate host responses to viral and neoplastic pathogens, and to prevent autoimmune destruction of host tissues. During the first four years of this R01 the applicant used the TCR alpha and beta genes as model systems to identify and characterize the transcription factors involved in regulating T cell development and activation. These studies have allowed the identification of several novel transcription factor families that appear to play important roles in regulating T cell- specific gene expression. These include the Ets protooncogenes, the GATA zinc finger proteins, and the CREB/ATF family of basic-leucine zipper transcription factors. There are at least 5 Ets proteins expressed in T cells: Ets-1, Elf-1, Fli-1, Ets-2, and GABPalpha. The available evidence suggests that the lymphoid-restricted factor, Ets-1 plays an important role in regulating the expression of genes such as TCR alpha and beta in developing thymocytes and resting T cells. In contrast, Elf-1 appears to play an important role in regulating a set of activation-specific T cell genes including GM-CSF, IL-3, IL-2Ralpha, and HIV-2. The applicant's previous studies have shown that Elf-1 is regulated at at least 3 post-translational levels: (i) by activation- specific phosphorylation, which is required for its DNA binding activity, (ii) by cooperative binding with specific AP1 and NF- kappaB transcription factors, and (iii) by regulated interactions with the retinoblastoma (Rb) gene product or related pocket proteins. Thus, Elf-1 appears to represent a functional link between activation-specific gene expression and cell cycle progression in T cells. Similarly, there are at least 6 ATF/CREB proteins expressed in T cells. Previous studies have suggested important roles for these proteins in regulating the expression of the TCR alpha and beta genes, and in controlling the activation-specific expression of molecules such as the proliferating cell nuclear antigen (PCNA), which is essential for cell cycle progression following T cell activation. In the studies described in this application, it is proposed to use a combination of genetic and biochemical approaches to more precisely elucidate the roles of Ets-1, Elf-1 and CREB/ATF transcription factors in regulating T cell development and activation. Specifically it is planned to (i) elucidate the molecular basis of Elf-1 activation following T cell activation, (ii) produce targeted disruptions of Ets-1 and Elf-1 in mice and study their effects on T cell development and activation, and (iii) use transgenic mice overexpressing a dominant-negative form of the CREB transcription factor to better define the role of CREB/ATF proteins in regulating T cell development and activation. These studies should have important implications regarding our understanding of the role of Ets and CREB/ATF transcription factors in regulating both T cell development and function. In addition, they may help to shed light on the molecular mechanisms involved in coordinately regulating gene expression and cell cycle progression in response to receptor-mediated signaling events.
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