The programmed cell death 1 protein (PD1) is an inhibitory receptor expressed on antigen activated T-cells that plays a critical role in the induction and maintenance of immune tolerance to self-antigens. Upon binding to its ligands CD274/PDCD1L1 (PD-L1) and CD273/PDCD1LG2 (PD-L2), PD1 is phosphorylated within its immunoreceptor tyrosine-based switch motif (ITSM), which facilitates the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2. PTPN11/SHP-2 then dephosphorylates key T-cell receptor (TCR) proximal signaling molecules, including ZAP70, PRKCQ/PKC theta and CD247/CD3 zeta, leading to the direct inhibition of T-cell activation. The PD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and evade destruction by the immune system, thereby facilitating tumor survival.
