The TCR-mediated signals leading to IL-2 production by T cell lines and naive T cells have been well characterized; however, the biochemical signaling mechanisms leading to disparate functions such as differentiation, effector cytokine production, death, and dysfunction due to immune pathologies are not known. In this review, we highlight recent studies that have identified specific alterations in proximal and distal TCR-coupled signaling and in the configuration of the TCR-signaling complex that occur as a result of T cell differentiation, and that have been associated with T cell dysfunctions in a number of diseases. We discuss how these specific alterations directly couple to disparate functions, and how these findings suggest that primary control of T cell functional outcomes can be traced to alterations in the activation state, configuration, and functional coupling of T cell-specific signaling intermediates.

T cell activation triggered via contact of the TCR with Ag/MHC is mediated by a series of biochemical events that transduce signals from the surface TCR to the nucleus, leading to activation of gene transcription for T cell proliferation and differentiation. TCR-coupled signaling leading to IL-2 production has been extensively characterized using the human T cell leukemia line Jurkat (1), which for over 20 years has been the model system of choice for dissecting the biochemical connections comprising TCR-coupled signal transduction. However, T cells can also mediate a variety of other functions depending on their activation/differentiation state and mode of activation, and T cells contribute to a variety of immune pathologies in autoimmune diseases. What is lacking in our knowledge of TCR-coupled signal transduction is a biochemical map of the routes that TCR-coupled signaling molecules follow to disparate functional destinations such as effector cytokine production, death, survival, anergy, memory, and T cell pathology. TCR-coupled signaling comprises a series of phosphorylation events, kinase activation, and recruitment events, leading to the formation of molecular complexes that deliver sequential and converging biochemical messages from cytoplasm to nucleus. TCR ligation by Ag/MHC results in the phosphorylation of TCR-associated CD3 subunits, such as CD3 and CD3, by members of the src family kinase family, p56lck and p59fyn. Phos-