- T cell-mediated immune responses are in- itiated by interaction of antigen bound to a glycoprotein encoded by the major histocompatibiity complex with the T cell antigen receptor (TCR). These recognition and binding steps are followed by multiple intracellular bi- ochemical events. The earliest event detected is an in- crease in intracellular protein tyrosine phosphorylation that involves a complex interaction of tyrosine kinases and phosphatases. Subsequently, one observes an increase in protein serine/threonine phosphorylation, phos- pholipid hydrolysis, and changes in intracellular Ca2� levels. These and other biochemical changes lead to cell proliferation, differentiation, and acquisition of effector functions. While binding of extracellular growth factors to receptors containing cytoplasmic protein tyrosine kinase (PTK) domains induces direct activation of their kinase activity, the multichain TCR lacks an intrinsic kinase domain and therefore represents a distinct type of receptor. It transduces signals via the interaction with, and activation of, non-receptor PTKs. Recent efforts directed at defining the TCR-linked signaling pathways have provided insight into the regulatory role of three PTKs, and the functional importance of some unique protein motifs in both TCR subunits and PTKs, which mediate critical protein-protein interactions in this path- way.J. Leukoc. Biol. 55: 265-271; 1994.