Figure 1. Unique spatiotemporal regulation of CTLA-4 and PD-1.

Activation of a naïve T cell requires TCR-mediated signals and costimulatory signals, generated by CD28:B7 ligand interactions. Upon activation, T cells induce expression of the inhibitory receptors CTLA-4 and PD-1, and the relative balance of stimulatory and inhibitory signaling can dictate the outcome of the T cell response. When CTLA-4- and PD-1-mediated inhibitory signals dominate, T cell activation is aborted, resulting in an unresponsive anergic state. Tregs can tip the balance toward inhibitory signals by removing B7 ligands from the APC surface via transendocytosis, thus favoring B7 ligand sequestration by the higher-affinity CTLA-4 receptor. When TCR- and CD28-mediated stimulatory signals dominate, T cells undergo clonal expansion, acquisition of effector function, and trafficking through nonlymphoid tissues. Effector T cell function can be limited by PD-1 interaction, with PD-L1 expressed on the surface of nonhematopoietic cells, including many different tumors. Moreover, PD-1:PD-L1 interactions can enhance Treg function, resulting in an additional layer of effector T cell inhibition.