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Mol Cell Biol. 2005 Nov;25(21):9543-53.

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

Author information

1
Abramson Family Cancer Research Institute, 556 BRB II/III, 421 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104, USA.

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.

PMID:
16227604
PMCID:
PMC1265804
DOI:
10.1128/MCB.25.21.9543-9553.2005
[Indexed for MEDLINE]
Free PMC Article

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