T CELL RECEPTOR SIGNALING BY PHOSPHORYLATED FORMS OF TCR

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DESCRIPTION (Adapted from Investigator's Abstract): The T cell receptor (TCR) zeta subunit, a component of the TCR complex, plays a critical role in TCR-mediated signal transduction. Following TCR engagement, the TCR-zeta subunit is phosphorylated on multiple tyrosine residues, resulting in the formation of two phosphorylated forms of 21 and 23 kDa. Recent studies have provided correlative evidence that the specific types of TCR zeta forms differ in their ability to couple to downstream effector molecules. Such differences are proposed to influence the processes of T cell development, the types of cytokines secreted by the T cells, and contribute to T cell anergy. The overall goal of this proposal is to understand how the formation of the 21 and 23 kDa phosphorylated species of the TCR zeta subunit affects TCR-mediated responses. The functional contribution of these phosphorylated forms of TCR zeta will be determined by selectively eliminating the formation of one or the other form in T cells and assessing the effects of these modifications on T cell development, TCR-mediated signal transduction, and T cell energy induction. Characterizing the regulation of TCR zeta phosphorylation, ZAP-70 recruitment and activation, and the interaction of the 21 and 23 kDa phosphorylated forms of TCR zeta with additional effector molecules is vital to our understanding of how these phosphorylated forms function during normal and pathological processes. The information derived from the proposed studies will have implications in regulating immune responses during T cell development, autoimmune diseases, allergic responses, and viral modulation of immune cells.