PMID- 33326785
OWN - NLM
STAT- MEDLINE
DCOM- 20211221
LR  - 20220429
IS  - 2211-1247 (Electronic)
VI  - 33
IP  - 11
DP  - 2020 Dec 15
TI  - Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
PG  - 108500
LID - S2211-1247(20)31489-3 [pii]
LID - 10.1016/j.celrep.2020.108500 [doi]
AB  - 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.
CI  - Copyright (c) 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Quinn, William J 3rd
AU  - Quinn WJ 3rd
AD  - Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, 
      University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Jiao, Jing
AU  - Jiao J
AD  - Division of Nephrology and Department of Pediatrics, Children's Hospital of 
      Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - TeSlaa, Tara
AU  - TeSlaa T
AD  - Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, 
      Princeton University, Washington Road, Princeton, NJ 08544, USA.
FAU - Stadanlick, Jason
AU  - Stadanlick J
AD  - Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine 
      at the University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Wang, Zhonglin
AU  - Wang Z
AD  - Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, 
      Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, 
      PA 19104, USA.
FAU - Wang, Liqing
AU  - Wang L
AD  - 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.
FAU - Akimova, Tatiana
AU  - Akimova T
AD  - 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.
FAU - Angelin, Alessia
AU  - Angelin A
AD  - Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104, USA.
FAU - Schafer, Patrick M
AU  - Schafer PM
AD  - Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104, USA.
FAU - Cully, Michelle D
AU  - Cully MD
AD  - Division of Nephrology and Department of Pediatrics, Children's Hospital of 
      Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Perry, Caroline
AU  - Perry C
AD  - Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, 
      University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Kopinski, Piotr K
AU  - Kopinski PK
AD  - Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104, USA.
FAU - Guo, Lili
AU  - Guo L
AD  - 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.
FAU - Blair, Ian A
AU  - Blair IA
AD  - 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.
FAU - Ghanem, Louis R
AU  - Ghanem LR
AD  - Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, 
      Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 
      19104, USA.
FAU - Leibowitz, Michael S
AU  - Leibowitz MS
AD  - Division of Oncology, Department of Pediatrics, Perelman School of Medicine at 
      the University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Hancock, Wayne W
AU  - Hancock WW
AD  - 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.
FAU - Moon, Edmund K
AU  - Moon EK
AD  - Department of Medicine, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Levine, Matthew H
AU  - Levine MH
AD  - Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, 
      Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, 
      PA 19104, USA.
FAU - Eruslanov, Evgeniy B
AU  - Eruslanov EB
AD  - Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine 
      at the University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Wallace, Douglas C
AU  - Wallace DC
AD  - Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104, USA.
FAU - Baur, Joseph A
AU  - Baur JA
AD  - Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, 
      University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Beier, Ulf H
AU  - Beier UH
AD  - Division of Nephrology and Department of Pediatrics, Children's Hospital of 
      Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA. 
      Electronic address: beieru@email.chop.edu.
LA  - eng
GR  - R01 CA187392/CA/NCI NIH HHS/United States
GR  - R01 DK098656/DK/NIDDK NIH HHS/United States
GR  - R01 MH108592/MH/NIMH NIH HHS/United States
GR  - T32 AI055428/AI/NIAID NIH HHS/United States
GR  - R01 DK106243/DK/NIDDK NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - F32 DK118856/DK/NIDDK NIH HHS/United States
GR  - R56 AI095276/AI/NIAID NIH HHS/United States
GR  - R01 OD010944/OD/NIH HHS/United States
GR  - R01 NS021328/NS/NINDS NIH HHS/United States
GR  - R01 AG043483/AG/NIA NIH HHS/United States
GR  - P01 AI073489/AI/NIAID NIH HHS/United States
GR  - K08 AI095353/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 0U46U6E8UK (NAD)
RN  - 33X04XA5AT (Lactic Acid)
SB  - IM
MH  - Cell Proliferation
MH  - Humans
MH  - Lactic Acid/*metabolism
MH  - NAD/*metabolism
MH  - Oxidation-Reduction
PMC - PMC7830708
MID - NIHMS1657050
OTO - NOTNLM
OT  - 3-phosphoglycerate
OT  - T cell metabolism
OT  - glycolysis
OT  - immunometabolism
OT  - lactate metabolism
OT  - nicotinamide adenine dinucleotide
OT  - redox metabolism
OT  - serine
COIS- Declaration of Interests The authors declare no competing interests.
EDAT- 2020/12/17 06:00
MHDA- 2021/12/22 06:00
PMCR- 2021/01/25
CRDT- 2020/12/16 20:06
PHST- 2020/01/17 00:00 [received]
PHST- 2020/10/08 00:00 [revised]
PHST- 2020/11/18 00:00 [accepted]
PHST- 2020/12/16 20:06 [entrez]
PHST- 2020/12/17 06:00 [pubmed]
PHST- 2021/12/22 06:00 [medline]
PHST- 2021/01/25 00:00 [pmc-release]
AID - S2211-1247(20)31489-3 [pii]
AID - 10.1016/j.celrep.2020.108500 [doi]
PST - ppublish
SO  - Cell Rep. 2020 Dec 15;33(11):108500. doi: 10.1016/j.celrep.2020.108500.