Figure 1. B7 and CD28 family members deliver costimulatory and coinhibitory signals to T cells.

(A) T cells are activated when their TcR and CD28 receive antigen-specific signals delivered by peptide/MHC complexes (pMHC) and costimulatory signals such as CD80 (B7.1), respectively. Activated T cells up-regulate PD-1 and can then be suppressed by interaction with PD-L1⁺ cells. Signaling through PD-1 results in T cell apoptosis, exhaustion, and/or anergy, and involves phosphorylation of SHP2 which blocks the activation of ZAP70, AKT, PI3K, and PKCΘ which mediate the down-stream events that culminate in activation through the TcR. PD-1 signaling also activates Cbl-b and Smad3 which down-regulate cell surface expression of the TcR and cell proliferation, respectively, inhibits the anti-apoptotic gene Bcl-xL, and activates the pro-apoptotic gene Bim. PD-L1 also tolerizes peripheral T cells by reverse signaling through T cell-expressed CD80. Green and red lines indicate pathways that are activated and suppressed, respectively. (B) Crystal structure of the extracellular PD-L1:PD-1 complex (human PD-L1 and murine PD-1). PD-L1 (shown in red) consists of extracellular IgV and IgC domains. PD-1 (shown in blue) consists of a single extracellular IgV-like domain. (Structure is from (79)).