T cells are an essential component of the immune system, recognizing the presence of foreign pathogens and setting in motion very specific intracellular responses to protect the body from serious infection. The T cell receptor (TCR) complex controls these T cell processes. It discriminates very subtle differences in the foreign molecules that it binds to, responding by activating the appropriate intracellular signals that will lead to an effective immune response. The underlying objective of this application is to understand exactly how the T cell receptor controls T cell development and immune functions. This is critical because failure to activate an appropriate response leads to serious infections and inappropriate activation leads to autoimmune diseases. This proposal focuses on the role of the TCRzeta subunit, and the deceptively simple phosphorylation of specific tyrosine residues that is at the core of the TCR's ability to regulate T cell development and immune functions. The TCRzeta subunit forms two discrete tyrosine phosphorylated forms of 21 and 23 kDa (p21 and p23). Preliminary results using a series of transgenic mice that differentially express these phosphorylated proteins indicate that p21 and p23 possess essential non-redundant functions in controlling T cell development, survival, and functions during infections. There are four specific aims in this proposal. The first is to identify the molecular mechanism(s) responsible for the different functions of p21 and p23. The second involves delineating the contribution of p21 to T cell survival. In the third, the functional contribution of phosphorylated zeta to T cells during immune responses to bacterial infections will be determined. The forth aim involves a characterization of phosphatases and kinases that regulate TCR functions. The approaches will incorporate sophisticated biochemical and 3-d imaging studies with the various TCRzeta transgenic lines. The studies will include immunological assays to monitor lymphocyte functions during normal lymphocyte development as well as during infections and autoimmune scenarios.
