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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD
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Antigens, Differentiation / physiology*
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Antigens, Surface / physiology*
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Apoptosis Regulatory Proteins / physiology*
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CD28 Antigens / metabolism
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CD3 Complex / metabolism
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CTLA-4 Antigen
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Enzyme Activation
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Gene Expression Regulation
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Humans
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In Vitro Techniques
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Lymphocyte Activation / physiology*
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Okadaic Acid / pharmacology
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Oncogene Protein v-akt / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositols / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Programmed Cell Death 1 Receptor
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Signal Transduction / drug effects
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Signal Transduction / physiology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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T-Lymphocytes / physiology*
Substances
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Antigens, CD
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Antigens, Differentiation
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Antigens, Surface
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Apoptosis Regulatory Proteins
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CD28 Antigens
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CD3 Complex
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CTLA-4 Antigen
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CTLA4 protein, human
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PDCD1 protein, human
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Phosphatidylinositols
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Phosphoinositide-3 Kinase Inhibitors
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Programmed Cell Death 1 Receptor
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Okadaic Acid
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Oncogene Protein v-akt
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Phosphoprotein Phosphatases