Figure 2.

PD-1 and PD-L1 interactions and mechanism of T cell inhibition. (A) PD-1 ligation to PD-L1 leads to recruitment of SHP2 by its intracellular signaling motif, ITSM. SHP2 exerts its inhibitory action on proximal signaling molecules of T cell receptor (TCR) such as LCK, ZAP70 resulting PI3K pathway inhibition. PI3K pathway is also inhibited through PTEN by inhibiting CK2. PLC-γ1 and PKCθ are also inhibited results in RAS pathway inhibition, decrease production of IL-2, and reduce expression of several transcription factors such NFAT, NFκB, and AP-1. (B) PD-1 also up-regulate Cbl-b and transcription factor BATF. (C) The outcome is inhibition of two main signaling pathways PI3K-AKT-mTOR and RAS-MEK-ERK which results in decreased cell division, growth, proliferation, differentiation, and survival. (D) Inhibition of these pathways also lead in altered T cell metabolism with increased inhibition of glycolysis, mitochondrial and amino acid metabolism, and increased fatty acid oxidation. (E) Reverse signaling through PD-L1 can also occur in tumor cells and antigen presenting cells (APCs) resulting in PI3K pathway up-regulation and enhanced glycolysis in cancers, and increased IL-10 production in DCs.