T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse.

Part 1 of this review will highlight the basic components and signaling pathways by which the T-cell antigen receptor (TCR) activates mature extrathymic T cells. TCR signaling commences with an early wave of protein tyrosine kinase activation, which is mediated by the Src kinases Lck and Fyn, the 70-kd zeta-associated protein kinase, and members of the Tec kinase family. This early wave of protein tyrosine phosphorylation leads to the activation of downstream signaling pathways, including an increase in intracellular free calcium, protein kinase C, nuclear factor kappaB and Ras-mitogen-activated protein kinase activation. These pathways activate transcription factors, such as activator protein 1, nuclear factor of activated T cells, and Rel proteins, which ultimately lead to the expression of genes that control cellular proliferation, differentiation, anergy, or apoptosis. This review also describes how costimulatory receptors assist in signal transduction and assembly of macromolecular complexes at the TCR contact site with the antigen-presenting cell, also known as the immune synapse. These basic concepts of TCR signal transduction will be used in part 2 to explain how T-cell function can be altered by therapeutic targeting of TCR signaling components, as well as to explain modification of TCR signaling during T(H)1/T(H)2 differentiation, tolerance, and immune senescence.