title: PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.
abstract: During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade.
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Nikolaos
authors: N
authors: Patsoukis
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Kankana
authors: K
authors: Bardhan
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Pranam
authors: P
authors: Chatterjee
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Duygu
authors: D
authors: Sari
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Bianling
authors: B
authors: Liu
authors: Metabolon, Inc., 617 Davis Drive, Suite 400, Durham, North Carolina 27713, USA.
authors: Lauren N
authors: LN
authors: Bell
authors: Metabolon, Inc., 617 Davis Drive, Suite 400, Durham, North Carolina 27713, USA.
authors: Edward D
authors: ED
authors: Karoly
authors: Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02284-9168, USA.
authors: Gordon J
authors: GJ
authors: Freeman
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Victoria
authors: V
authors: Petkova
authors: 1] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Centerr, Harvard Medical School, 330 Brookline Avenue, Dana 513-517, Boston, Massachusetts 02215, USA.
authors: Pankaj
authors: P
authors: Seth
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Lequn
authors: L
authors: Li
authors: 1] Division of Hematology-Oncology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Beth Israel Deaconess Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors: Vassiliki A
authors: VA
authors: Boussiotis
mesh_terms: D060890:B7-H1 Antigen / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008066:Lipolysis; D008213:Lymphocyte Activation; D010084:Oxidation-Reduction; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D005227:Fatty Acids; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase