T-Cell Activation and Tolerance

Activation of T lymphocytes during an immune response triggers a series of programmed gene regulation, proliferation, differentiation, and effector functions. These T-cell functions coordinate with other leukocytes to permit the immune system to react against foreign antigens without initiating self-reactivity or autoimmunity. Each of these functions is fully dependent on environmental cues that are recognized by cell surface receptors and are then translated through biochemical alterations within the cell. This chapter discusses signal transduction through one of the most studied of these receptors, the antigen-specific T-cell receptor (TCR) complex. It addresses the mechanisms whereby signals propagated through the TCR combine with those from costimulatory receptors to produce either productive 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 these molecular pathways has resulted in several clinically relevant drugs currently used to treat autoimmunity, transplant rejection, and cancer.