The antigen specific cells of the immune system, the T and B lymphocytes, express multi-subunit cell surface receptors that are essential for recognizing and responding to pathogens such as viruses, bacteria, and parasites. We are studying the signal transduction pathways that are triggered following interactions between these receptors and the appropriate target molecules. Receptor stimulation activates a cascade of intracellular signals that are regulated by different families of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases). For T cells, effective receptor signaling will elicit diverse biological outcomes such as lymphokine release and cytotoxic functions. However, incomplete or attenuated signals may promote T cell death and/or anergy induction, and in the thymus, may be important for the development of the T cell repertoire. The TCR z molecule, a component of the TCR complex, is one of the many tyrosine phosphorylated proteins that develops following TCR ligation. A prevailing hypothesis is that certain phosphorylated intermediates of the TCR z subunit control many of these biological processes. We have been using mice that are genetically deficient in selected tyrosine phosphorylated intermediates of the TCR z molecule. Our studies of these mice have revealed very surprising and dramatic results concerning the mechanisms of TCR signal transmission. We are currently pursuing several related questions. 1) What are the functional roles of the distinct tyrosine phosphorylated intermediates of the TCR z subunit? 2) How are TCR signaling processes regulated by the different families of protein kinases ? 3) How do differences in the signals generated through the TCR promote very distinct biological outcomes, immune-responsiveness or non-responsiveness ? 4) How does the protein tyrosine phosphatase PTPH1 attenuate TCR signaling processes? With answers to these questions, we hope to gain a better understanding of the mechanisms of T cell development and T cell effector functions during normal and disease conditions.
