PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation, 2015, Patsoukis et al

PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation
Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA

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.

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Results subheadings —

• PD-1 abrogates transport and utilization of glucose
• PD-1 inhibits amino acid transport and metabolism
• PD-1 induces upregulation of CPT1A and FAO
• PD-1 induces lipolysis and b-oxidation of endogenous fatty acids
• Substantial mitochondrial SRC on PD-1 ligation
• CTLA-4 inhibits glycolytic metabolism without enhancing FAO
• PD-1 switches the glycolytic programme of pre-activated T cells

PD-1 is programmed cell death protein 1
CPT1A is carnitine palmitoyltransferase I
CTLA-4 is cytotoxic T-lymphocyte-associated protein 4 (CD152)
FAO is fatty acid oxidation
SRC is spare respiratory capacity (extra mitochondrial capacity available in the cell to produce energy under conditions of stress)