NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function.

Natural Killer T-Cells / metabolism Interleukin-4 / metabolism Glutamine / metabolism AMP-Activated Protein Kinases / metabolism Interferon-gamma / metabolism Homeostasis Hexosamines / metabolism Phenotype TOR Serine-Threonine Kinases / metabolism Mechanistic Target of Rapamycin Complex 1 / metabolism Nitrogen / metabolism Glutathione / metabolism
CP: Immunology HBP PPP ROS glutathione glycosylation metabolism

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
25 10 2022
Historique:
received: 12 10 2021
revised: 19 05 2022
accepted: 26 09 2022
entrez: 26 10 2022
pubmed: 27 10 2022
medline: 29 10 2022
Statut: ppublish

Résumé

Natural killer T (NKT) cells operate distinctly different metabolic programming from CD4 T cells, including a strict requirement for glutamine to regulate cell homeostasis. However, the underlying mechanisms remain unknown. Here, we report that at a steady state, NKT cells have higher glutamine levels than CD4 T cells and that NKT cells increase glutaminolysis on activation. Activated NKT cells use glutamine to fuel the tricarboxylic acid cycle and glutathione synthesis. In addition, glutamine-derived nitrogen enables protein glycosylation via the hexosamine biosynthesis pathway (HBP). Each of these branches of glutamine metabolism seems to be critical for NKT cell homeostasis and mitochondrial functions. Glutaminolysis and HBP differentially regulate interleukin-4 (IL-4) and interferon γ (IFNγ) production. Glutamine metabolism appears to be controlled by AMP-activated protein kinase (AMPK)-mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight a distinct metabolic requirement of NKT cells compared with CD4 T cells, which may have therapeutic implications in the treatment of certain nutrient-restricted diseases.

Identifiants

DOI: 10.1016/j.celrep.2022.111516 PMID: 36288696 PMC: PMC9664378
pubmed: 36288696
pii: S2211-1247(22)01366-3
doi: 10.1016/j.celrep.2022.111516
pmc: PMC9664378
mid: NIHMS1845177
pii:
doi:

Substances chimiques

Interleukin-4 207137-56-2
Glutamine 0RH81L854J
AMP-Activated Protein Kinases EC 2.7.11.31
Interferon-gamma 82115-62-6
Hexosamines 0
TOR Serine-Threonine Kinases EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 1 EC 2.7.11.1
Nitrogen N762921K75
Glutathione GAN16C9B8O

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

111516

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI148289
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248160
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI121156
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK097153
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA237421
Pays : United States

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests C.A.L. has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to K-Ras-regulated metabolic pathways and redox-control pathways in cancer and targeting the glutamic-oxaloacetic transaminase 1 (GOT1) pathway as a therapeutic approach.

Références

J Biol Chem. 2004 Jan 23;279(4):2737-46
pubmed: 14576155
PLoS One. 2013;8(3):e60217
pubmed: 23533675
J Immunol. 2015 Jan 1;194(1):223-30
pubmed: 25404366
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):E776-83
pubmed: 24516149
Immunity. 2013 Feb 21;38(2):225-36
pubmed: 23415911
J Immunol. 2000 Apr 15;164(8):4375-81
pubmed: 10754338
Science. 2009 May 22;324(5930):1029-33
pubmed: 19460998
Immunity. 2017 Apr 18;46(4):675-689
pubmed: 28423341
J Immunol. 2003 Aug 15;171(4):1637-41
pubmed: 12902459
J Exp Med. 2004 May 3;199(9):1213-21
pubmed: 15123743
Cancer Cell. 2012 Nov 13;22(5):631-44
pubmed: 23153536
Front Immunol. 2019 Jan 14;9:3036
pubmed: 30692989
Eur J Immunol. 2017 Mar;47(3):516-526
pubmed: 28078715
Cell. 2016 Oct 20;167(3):829-842.e13
pubmed: 27745970
Mol Cell. 2010 May 28;38(4):487-99
pubmed: 20513425
Proc Natl Acad Sci U S A. 2014 May 13;111(19):7066-71
pubmed: 24785297
Cell Res. 2020 Aug;30(8):649-659
pubmed: 32709897
Nat Rev Drug Discov. 2013 Dec;12(12):931-47
pubmed: 24287781
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):
pubmed: 33753493
Mol Clin Oncol. 2016 Apr;4(4):607-610
pubmed: 27073674
Immunity. 2015 Apr 21;42(4):613-26
pubmed: 25862091
Nat Immunol. 2016 Jun;17(6):712-20
pubmed: 27111141
Cell. 2018 Dec 13;175(7):1780-1795.e19
pubmed: 30392958
Sci Rep. 2016 Sep 08;6:32606
pubmed: 27605385
Immunity. 2008 Sep 19;29(3):391-403
pubmed: 18703361
Elife. 2017 Jan 06;6:
pubmed: 28059703
J Immunol. 2004 Aug 1;173(3):2159-66
pubmed: 15265953
Nat Commun. 2020 Jan 23;11(1):438
pubmed: 31974378
Immunity. 2013 Apr 18;38(4):633-43
pubmed: 23601682
J Biol Chem. 2013 May 24;288(21):15121-30
pubmed: 23592772
Science. 1997 Nov 28;278(5343):1623-6
pubmed: 9374462
Nat Immunol. 2008 Sep;9(9):1055-64
pubmed: 18660811
Immunogenetics. 2016 Aug;68(8):639-48
pubmed: 27368411
J Immunol. 2014 Aug 15;193(4):1759-65
pubmed: 25015820
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12453-8
pubmed: 19617548
Cell. 2015 Sep 10;162(6):1217-28
pubmed: 26321681
J Clin Invest. 2013 Sep;123(9):3678-84
pubmed: 23999442
Mol Cell. 2010 Jul 30;39(2):171-83
pubmed: 20670887
Immunity. 2002 Apr;16(4):583-94
pubmed: 11970881
Eur J Immunol. 2015 Sep;45(9):2504-16
pubmed: 26114249
Cancer Res. 2017 Dec 1;77(23):6746-6758
pubmed: 29021138
Immunity. 2002 Dec;17(6):725-36
pubmed: 12479819
Cell. 2009 Feb 6;136(3):521-34
pubmed: 19203585
Int J Mol Sci. 2015 Sep 22;16(9):22830-55
pubmed: 26402672
Science. 2015 Jan 9;347(6218):194-8
pubmed: 25567907
Cell. 2013 Jun 6;153(6):1239-51
pubmed: 23746840
Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):E5678-87
pubmed: 25512546
Nature. 2009 Jul 2;460(7251):103-7
pubmed: 19494812
Curr Immunol Rev. 2012 Nov 1;8(4):287-296
pubmed: 25288922
Front Immunol. 2018 Jun 26;9:1450
pubmed: 29997620
J Immunol. 2011 May 15;186(10):5801-6
pubmed: 21478405
J Exp Med. 2003 Jun 16;197(12):1667-76
pubmed: 12796469
Immunity. 2015 Jan 20;42(1):41-54
pubmed: 25607458
BMC Complement Altern Med. 2012 Oct 30;12:201
pubmed: 23110507
Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7439-7448
pubmed: 30910955
J Immunol. 2017 Nov 15;199(10):3478-3487
pubmed: 29021374
Nat Immunol. 2013 Oct;14(10):1064-72
pubmed: 23955661
Nat Rev Immunol. 2021 Oct;21(10):637-652
pubmed: 33859379
Mol Pharmacol. 2005 Oct;68(4):1018-30
pubmed: 16037419
Oncogene. 2004 Apr 1;23(14):2507-22
pubmed: 14676829
Sci Signal. 2015 Sep 29;8(396):ra97
pubmed: 26420908
Cancer Cell. 2017 Mar 13;31(3):311-325
pubmed: 28292435
Exp Mol Med. 2020 Sep;52(9):1496-1516
pubmed: 32943735
J Immunol. 2010 Jul 15;185(2):1037-44
pubmed: 20554958
Mol Nutr Food Res. 2011 Jun;55(6):832-43
pubmed: 21538846
Front Cell Dev Biol. 2018 Sep 25;6:122
pubmed: 30320109
Mol Cell. 2012 Aug 10;47(3):349-58
pubmed: 22749528

Auteurs

Ajay Kumar (A)

Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, Ann Arbor, MI 48109, USA. Electronic address: ajkumar@umich.edu.

Emily L Yarosz (EL)

Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Anthony Andren (A)

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Li Zhang (L)

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Costas A Lyssiotis (CA)

Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Cheong-Hee Chang (CH)

Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, Ann Arbor, MI 48109, USA; Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: heechang@umich.edu.

Articles similaires

FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR.

Minle Li, Xuan Chen, Pengfei Qu et al.
1.00
Animals TOR Serine-Threonine Kinases Colorectal Neoplasms Colitis Mice

Lipid accumulation in adipose tissue-resident iNKT cells contributes to an inflammatory phenotype.

Imogen Morris, Frank Vrieling, Annemieke Bouwman et al.
1.00
Animals Natural Killer T-Cells Mice Adipose Tissue Lipid Metabolism

A key role for P2RX5 in brown adipocyte differentiation and energy homeostasis.

Maria Razzoli, Seth McGonigle, Bhavani Shankar Sahu et al.
1.00
Animals Adipocytes, Brown Mice Cell Differentiation Male

Causal linkage of Graves' disease with aging: Mendelian randomization analysis of telomere length and age-related phenotypes.

Jingwen Hu, Jin Zhang, Yingshu Liu et al.
1.00
Humans Mendelian Randomization Analysis Graves Disease Aging Genome-Wide Association Study

Classifications MeSH

questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Cellules T tueuses naturelles › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-4 › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Glutamine › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › AMP-Activated Protein Kinases › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Lymphokines › Facteurs d'activation des macrophages › Interféron gamma › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Glucides › Osamines › Hexosamine › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-1 cible mécanistique de la rapamycine › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Produits chimiques inorganiques › Gaz › Azote › NKT cells adopt a glutamine-addicted phenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Oligopeptides › Glutathion › NKT cells adopt a glutamine-addicted phenotype...