Cell Reports (Dec 2020)
Lactate Limits T Cell Proliferation via the NAD(H) Redox State
- William J. Quinn, III,
- Jing Jiao,
- Tara TeSlaa,
- Jason Stadanlick,
- Zhonglin Wang,
- Liqing Wang,
- Tatiana Akimova,
- Alessia Angelin,
- Patrick M. Schäfer,
- Michelle D. Cully,
- Caroline Perry,
- Piotr K. Kopinski,
- Lili Guo,
- Ian A. Blair,
- Louis R. Ghanem,
- Michael S. Leibowitz,
- Wayne W. Hancock,
- Edmund K. Moon,
- Matthew H. Levine,
- Evgeniy B. Eruslanov,
- Douglas C. Wallace,
- Joseph A. Baur,
- Ulf H. Beier
Affiliations
- William J. Quinn, III
- Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA
- Jing Jiao
- Division of Nephrology and Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Tara TeSlaa
- Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Washington Road, Princeton, NJ 08544, USA
- Jason Stadanlick
- Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Zhonglin Wang
- Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Liqing Wang
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Tatiana Akimova
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Alessia Angelin
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Patrick M. Schäfer
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Michelle D. Cully
- Division of Nephrology and Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Caroline Perry
- Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA
- Piotr K. Kopinski
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Lili Guo
- Penn SRP Center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Ian A. Blair
- Penn SRP Center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Louis R. Ghanem
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Michael S. Leibowitz
- Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Wayne W. Hancock
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Edmund K. Moon
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Matthew H. Levine
- Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
- Evgeniy B. Eruslanov
- Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Douglas C. Wallace
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Joseph A. Baur
- Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA
- Ulf H. Beier
- Division of Nephrology and Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
- Journal volume & issue
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Vol. 33,
no. 11
p. 108500
Abstract
Summary: Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression.
