T-Cell Activation and Tolerance

T-lymphocyte activities form the foundations of both the coordinated protective response to infection, and the establishment of immune system tolerance—the host’s ability to react against foreign antigens while restraining potentially damaging reactivity against self. Clonal populations of lymphocytes express unique somatically rearranged T-cell receptors (TCRs). The TCR complex allows cells to translate recognition of antigen into intracellular biochemical events that underpin cellular developmental programs as well as diverse effector functions such as proliferation, differentiation, cytokine secretion, cytotoxicity, and programmed cell death. This chapter addresses the mechanisms whereby signals propagated through the TCR combine with those emanating from costimulatory receptors and accessory molecules to produce either cellular activation or immune tolerance. It also discusses how abnormal TCR signaling, as well as imbalanced signaling through costimulatory or coinhibitor molecules, can contribute to T-cell dysfunction and disease. Targeting the TCR-engaged signaling machinery and TCR signal-driven gene transcriptional programs has yielded many novel therapeutics that have transformed management of broad swaths of immune-mediated or immune-modulated disease, including autoimmunity, malignancy, and cancer.