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Nat Commun. 2015 Mar 26;6:6692. doi: 10.1038/ncomms7692.

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

Author information

1
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.
2
Metabolon, Inc., 617 Davis Drive, Suite 400, Durham, North Carolina 27713, USA.
3
Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02284-9168, USA.
4
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.

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.

PMID:
25809635
PMCID:
PMC4389235
DOI:
10.1038/ncomms7692
[Indexed for MEDLINE]
Free PMC Article
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