CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms

TLDR

CTLA‑4 and PD‑1 are receptors that negatively regulate T‑cell activation. Ligation of CTLA‑4 and PD‑1 blocks CD3/CD28‑driven glucose metabolism and Akt activation through distinct pathways: CTLA‑4 suppresses Akt phosphorylation via PP2A, whereas PD‑1 inhibits PI3K/AKT signaling through its ITSM motif and more potently alters the T‑cell transcriptional profile, indicating complementary inhibitory mechanisms.

Abstract

CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.