T cell activation requires a TCR-mediated signal, but the strength, course, and duration are directed by costimulatory molecules and cytokines from the antigen-presenting cell (APC). An unexpected finding was that some molecular pairs attenuate the strength of the TCR signal, a process termed coinhibition (reviewed in refs. 1-3). The threshold for the initiation of an immune response is set very high, with a requirement for both antigen recognition and costimulatory signals from innate immune recognition of "danger" signals. Paradoxically, T cell activation also induces expression of coinhibitory receptors such as programmed death-1 (PD-1). Cytokines produced after T cell activation such as INF-γ and IL-4 up-regulate PD-1 ligands, establishing a feedback loop that attenuates immune responses and limits the extent of immune-mediated tissue damage unless overridden by strong costimulatory signals. PD-1 is a CD28 family member expressed on activated T cells, B cells, and myeloid cells. In proximity to the TCR signaling complex, PD-1 delivers a coinhibitory signal upon binding to either of its two ligands, PD-L1 or PD-L2.
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