title: CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 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.
authors.affiliation: Abramson Family Cancer Research Institute, 556 BRB II/III, 421 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Richard V
authors.initials: RV
authors.lastname: Parry
authors.forename: Jens M
authors.initials: JM
authors.lastname: Chemnitz
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Frauwirth
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Lanfranco
authors.forename: Inbal
authors.initials: I
authors.lastname: Braunstein
authors.forename: Sumire V
authors.initials: SV
authors.lastname: Kobayashi
authors.forename: Peter S
authors.initials: PS
authors.lastname: Linsley
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
mesh_terms: D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D060908:CTLA-4 Antigen; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; D019319:Okadaic Acid; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases; D061026:Programmed Cell Death 1 Receptor; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human