: T cell responses to microorganisms, neoplastic cells and normal self cells, as occurs in autoimmune diseases, are characterized by T cell clonal expansion and development of effector and memory function which is targeted toward the relevant foreign or self antigen. So as to design more effective drug therapies for the treatment of infectious diseases, cancer, and autoimmunity, it is important to understand the intracellular mechanisms by which signals received by different T cell surface receptors are able to instruct these responses. As in other cell types, numerous different classes of intracellular molecules are involved in signal transduction in T cells. Amongst these are cytoplasmic adapter proteins that function in signaling through the formation of signaling complexes with catalytically active molecules. One recently described adapter protein in T cells is the T cell-specific adapter protein (TSAd), also known as LCK-associated adapter protein (LAD) in mice. This molecule plays an important role in the induction of the T cell cytokines, interleukin-2 (IL-2), which drives T cell proliferation and memory formation, and interferon gamma (IFN-gamma), which is involved in the function of T helper-I-type effector T cells. How TSAd participates in intracellular signaling is unknown. However, we have demonstrated that TSAd is an atypical adapter protein that has a predominant nuclear localization that probably acts, at least in part, as a direct regulator of T cell gene transcription. The long-term objectives of this proposal are to understand in greater detail how TSAd controls the transcription of target genes. In these studies, we will focus upon two different domains of the protein, the Src homology-2 (SH2) domain and the amino-terminal region. In one Specific Aim, we will test the hypothesis the SH2 domain functions as a dynamic regulator of TSAd nuclear import and transcription activity through its ability to recognize a single tyrosine-phosphorylated ligand of p95-100 kDa. In a second Specific Aim, we will test the hypothesis that the amino-terminal region functions as a module that confers upon TSAd an ability to recognize specific DNA sequences in target gene promoters. The importance of these two domains for the transcription function of TSAd in primary T cells and for normal T cell immunity in whole animals will be tested in a third Specific Aim of this proposal. Together, these studies should lead to novel insights into mechanisms of T cell gene transcription control and, in addition, should highlight means by which aberrant T cell reactivity in certain types of T cell-mediated immune disease might be prevented.
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