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PMID: 25809635 Published · epublish English Journal Article Research Support, N.I.H., Extramural

PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.

Nature communications ·Vol. 6 ·2015-03-26 ·Pages 6692

Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA

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.

MeSH Terms
B7-H1 Antigen/pharmacology CD4-Positive T-Lymphocytes/metabolism Carnitine O-Palmitoyltransferase/genetics Cells, Cultured Fatty Acids/metabolism Glycolysis Humans In Vitro Techniques Lipid Metabolism Lipolysis Lymphocyte Activation Oxidation-Reduction Programmed Cell Death 1 Receptor/metabolism
Chemicals
B7-H1 Antigen CD274 protein, human Fatty Acids PDCD1 protein, human Programmed Cell Death 1 Receptor CPT1A protein, human Carnitine O-Palmitoyltransferase
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Patsoukis Nikolaos
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.
Bardhan Kankana
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.
Chatterjee Pranam
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.
Sari Duygu
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.
Liu Bianling
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.
Bell Lauren N
Metabolon, Inc., 617 Davis Drive, Suite 400, Durham, North Carolina 27713, USA.
Karoly Edward D
Metabolon, Inc., 617 Davis Drive, Suite 400, Durham, North Carolina 27713, USA.
Freeman Gordon J
Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02284-9168, USA.
Petkova Victoria
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.
Seth Pankaj
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.
Li Lequn
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.
Boussiotis Vassiliki A
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.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms7692
Published
2015-03-26
Epub
2015-00-26
Pages
6692
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4389235
Subset
IM
Grants
NIAID NIH HHS · AI098129 · United States
NIAID NIH HHS · P01 AI056299 · United States
NCI NIH HHS · R01 CA183605 · United States
NIAID NIH HHS · R56 AI098129 · United States
NCI NIH HHS · CA183605 · United States
NIAID NIH HHS · AI056299 · United States
PHS HHS · HHSN2722018C · United States
External Links
PubMed source DOI: 10.1038/ncomms7692 PMC Full Text View journal details
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