Lactate Limits T Cell Proliferation via the NAD(H) Redox State
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720314893 |
| _version_ | 1819143731251511296 |
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| author | 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 |
| author_facet | 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 |
| author_sort | William J. Quinn, III |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T12:30:54Z |
| format | Article |
| id | doaj.art-7bafd43031934dc89425250de8164ad0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T12:30:54Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7bafd43031934dc89425250de8164ad02022-12-21T18:25:40ZengElsevierCell Reports2211-12472020-12-013311108500Lactate Limits T Cell Proliferation via the NAD(H) Redox StateWilliam J. Quinn, III0Jing Jiao1Tara TeSlaa2Jason Stadanlick3Zhonglin Wang4Liqing Wang5Tatiana Akimova6Alessia Angelin7Patrick M. Schäfer8Michelle D. Cully9Caroline Perry10Piotr K. Kopinski11Lili Guo12Ian A. Blair13Louis R. Ghanem14Michael S. Leibowitz15Wayne W. Hancock16Edmund K. Moon17Matthew H. Levine18Evgeniy B. Eruslanov19Douglas C. Wallace20Joseph A. Baur21Ulf H. Beier22Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USADivision of Nephrology and Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USALewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Washington Road, Princeton, NJ 08544, USADivision of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USADivision 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, USADivision 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, USACenter for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USACenter for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADivision of Nephrology and Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAPenn 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, USAPenn 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, USADivision of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USADivision of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USADivision 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, USADepartment of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USADivision of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USACenter for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USADivision of Nephrology and Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720314893T cell metabolismglycolysisimmunometabolismnicotinamide adenine dinucleotidelactate metabolism3-phosphoglycerate |
| spellingShingle | 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 Lactate Limits T Cell Proliferation via the NAD(H) Redox State Cell Reports T cell metabolism glycolysis immunometabolism nicotinamide adenine dinucleotide lactate metabolism 3-phosphoglycerate |
| title | Lactate Limits T Cell Proliferation via the NAD(H) Redox State |
| title_full | Lactate Limits T Cell Proliferation via the NAD(H) Redox State |
| title_fullStr | Lactate Limits T Cell Proliferation via the NAD(H) Redox State |
| title_full_unstemmed | Lactate Limits T Cell Proliferation via the NAD(H) Redox State |
| title_short | Lactate Limits T Cell Proliferation via the NAD(H) Redox State |
| title_sort | lactate limits t cell proliferation via the nad h redox state |
| topic | T cell metabolism glycolysis immunometabolism nicotinamide adenine dinucleotide lactate metabolism 3-phosphoglycerate |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720314893 |
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