Abstract: FR-PO1013

Novel Approaches to Modulate T Cell Responses Based on Insights from Tumor Metabolism: Lactate and Pyruvate Control T Cell Function through NAD Redox Metabolism

Session Information

Category: Transplantation

  • 1701 Transplantation: Basic and Experimental

Authors

  • Beier, Ulf H., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Jiao, Jing, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Wang, Zhonglin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Quinn, William J, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Baur, Joseph A., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hancock, Wayne W., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Solid tumors can evade host immunity due to their distinctive metabolic properties; e.g. the tumor microenvironment can be glucose-depleted but rich in lactic acid, thereby weakening anti-tumor immunity, since cytotoxic and effector T cells require glycolysis to function. We questioned if such insights might suggest novel approaches for T cell suppression in transplant recipients.

Methods

We co-stimulated human and murine CD8+ and CD4+ T cells and exposed them to pH-neutral 5-40 mM sodium L-lactate, D-lactate, or pyruvate, using equimolar NaCl as a control, and measuring T cell proliferation and cytokine production (IL-2, IFN-g, IL-17), and bioenergetics profiles by Seahorse. We measured nicotinamide adenine dinucleotide both in oxidized (NAD+) and reduced (NADH) form, and tested the effects of drugs that oxidize NAD (alpha-ketobutyrate, beta-lapachone, pyrroloquinoline quinone), or impair NAD recycling (FK 866) or NAD oxidation/reduction via lactate dehydrogenase (LDH) inhibition (GSK 2837808A). We induced a tumor-like glycolytic metabolism in MHC-mismatched cardiac allografts by perfusing BALB/c hearts with UW solution containing 1 mM phenformin, 1-2 μM oligomycin, 2 μM nicolsamide, or 2.5 μM UK5099 for 1 hour prior to their engraftment in untreated C57BL/6 recipients.

Results

Sodium L- (& D-) lactate reduced NAD+ to NADH in an LDH(D)-dependent manner, impaired T cell proliferation, and increased induced Foxp3+ Treg formation. Sodium pyruvate achieved the opposite, oxidized NADH to NAD+, reduced iTreg formation, and increased effector T cell proliferation. Bioenergetic measurements showed that in activated effector T cells, NAD+ oxidation increased, while NADH reduction impaired glycolysis, showing that T cell function depends on the NAD:NADH redox status, and less on the absolute amount of NAD. Interestingly, transiently inducing a glycolytic metabolism in MHC-mismatched cardiac allografts prolonged allograft survival for several days.

Conclusion

NAD redox metabolism controls T cell function through aerobic glycolysis, and inducing glycolytic metabolism in cardiac allografts can promote allograft survival. These data provide a rationale for testing further approaches to modulate NAD redox metabolism in allograft recipients.

Funding

  • Other NIH Support