CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms

Richard V. Parry, Jens M. Chemnitz, Kenneth A. Frauwirth, Anthony R. Lanfranco, Inbal Braunstein, Sumire V. Kobayashi, Peter S. Linsley, Craig B. Thompson, James L. Riley

Research output: Contribution to journalArticlepeer-review

1084 Scopus citations


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 PDK 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.

Original languageEnglish (US)
Pages (from-to)9543-9553
Number of pages11
JournalMolecular and cellular biology
Issue number21
StatePublished - Nov 2005
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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