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

• Published in: Blood Vol. 104; no. 11; p. 2657
• Main Authors: Chemnitz, Jens M., Riley, James L., Frauwirth, Kenneth A., Braunstein, Inbal, Kobayashi, Sumire V., Linsley, Peter S., Thompson, Craig B., Parry, Richard V.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16-11-2004
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V104.11.2657.2657

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/Atk activation was dependent upon the ITSM located in its cytoplasmic tail. Lastly, PD-1 ligation is more effective in suppressing CD3/28 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.