Figure 2: PD-1 and CTLA-4 target different molecules to inhibit T cell activation. Upon T cell conjugates with APC, PD-1 is located in the immune synapse at the T-APC interface and recruits SHP2 to inhibit TCR-induced activation of the PI3K-Akt and Ras-MEK/ERK pathways. PD-1 also suppresses transcription of SKP2 to result in accumulation of p27kip1, which is an inhibitor of cyclindependent kinases to block cell cycle and proliferation. Ligation of CTLA-4 dephosphorylates TCRζ chain and other signaling molecules including CD3ε, ZAP70 and Fyn. CTLA-4 inhibits Akt phosphorylation and activation by recruiting PP2A to its cytoplasmic tail. Ligation of CTLA-4 phosphorylates the pro-apoptotic factor BAD and enhances BcL-XL activity to prevent T cell apoptosis.