Carbon source availability drives nutrient utilization in CD8+ T cells.
| Title: | Carbon source availability drives nutrient utilization in CD8+ T cells. |
|---|---|
| Authors: | Kaymak I; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Luda KM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Blegdamsvej 3B, 2200 København, Denmark.; Duimstra LR; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Ma EH; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Longo J; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Dahabieh MS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Faubert B; Department of Medicine-Hematology and Oncology, University of Chicago, Chicago, IL, USA.; Oswald BM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Watson MJ; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Kitchen-Goosen SM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; DeCamp LM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Compton SE; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Fu Z; Bioinformatics and Biostatistics Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; DeBerardinis RJ; Children's Medical Center Research Institute, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA.; Williams KS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Sheldon RD; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Metabolomics and Bioenergetics Core Facility, Van Andel Institute, Grand Rapids, MI, USA.; Jones RG; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA. Electronic address: russell.jones@vai.org. |
| Source: | Cell metabolism [Cell Metab] 2022 Sep 06; Vol. 34 (9), pp. 1298-1311.e6. Date of Electronic Publication: 2022 Aug 17. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Cambridge, Mass. : Cell Press, c2005- |
| MeSH Terms: | CD8-Positive T-Lymphocytes*/metabolism ; Carbon*/metabolism; Glucose/metabolism ; Lactic Acid/metabolism ; Nutrients |
| Abstract: | How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells.; (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests R.J.D. is a founder and consultant for Atavistik Biosciences and an advisor for Agios Pharmaceuticals, Nirogy Therapeutics, and Vida Ventures. R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics. |
| References: | Cancer Cell. 2021 Jan 11;39(1):28-37. (PMID: 33125860); Elife. 2019 Apr 16;8:. (PMID: 30990168); Immunity. 2019 Nov 19;51(5):856-870.e5. (PMID: 31747582); Immunity. 2002 Jun;16(6):769-77. (PMID: 12121659); J Immunol. 2011 Nov 15;187(10):4967-78. (PMID: 21987662); Blood. 1981 Feb;57(2):324-7. (PMID: 6969615); Immunity. 2022 Jan 11;55(1):14-30. (PMID: 35021054); J Mass Spectrom. 1996 Mar;31(3):255-62. (PMID: 8799277); Blood. 2007 May 1;109(9):3812-9. (PMID: 17255361); Sci Adv. 2019 Jan 02;5(1):eaau7314. (PMID: 30613774); Blood. 2010 Jun 10;115(23):4742-9. (PMID: 20351312); Nucleic Acids Res. 2012 Jan;40(Database issue):D809-14. (PMID: 22139941); Nat Rev Immunol. 2015 Nov;15(11):705-16. (PMID: 26449178); Immunity. 2021 Apr 13;54(4):829-844.e5. (PMID: 33705706); Nature. 2021 Mar;591(7851):645-651. (PMID: 33589820); Can J Biochem Physiol. 1959 Aug;37(8):911-7. (PMID: 13671378); Mol Ther Methods Clin Dev. 2022 Feb 15;24:380-393. (PMID: 35284590); Nat Rev Immunol. 2017 Oct;17(10):608-620. (PMID: 28669986); Nature. 2014 Apr 3;508(7494):108-12. (PMID: 24670634); Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6047-6055. (PMID: 32123114); Immunity. 2017 May 16;46(5):703-713. (PMID: 28514672); Cell Metab. 2016 Mar 8;23(3):517-28. (PMID: 26853747); Science. 2009 Jan 23;323(5913):502-5. (PMID: 19164748); Sci Immunol. 2018 Sep 7;3(27):. (PMID: 30194241); Dis Model Mech. 2018 Aug 7;11(8):. (PMID: 30104199); Cell Metab. 2017 Jun 6;25(6):1282-1293.e7. (PMID: 28416194); Bioinformatics. 2014 May 1;30(9):1333-5. (PMID: 24413674); Immunity. 2019 Dec 17;51(6):1074-1087.e9. (PMID: 31784108); Cell Metab. 2016 Nov 8;24(5):657-671. (PMID: 27641098); Clin Chim Acta. 1975 May 1;60(3):379-83. (PMID: 1079760); Cell Metab. 2017 Feb 7;25(2):345-357. (PMID: 28111214); Nat Rev Immunol. 2012 Nov;12(11):749-61. (PMID: 23080391); Science. 2009 May 22;324(5930):1029-33. (PMID: 19460998); Cell. 2017 Apr 06;169(2):258-272.e17. (PMID: 28388410); Nat Metab. 2022 Jan;4(1):141-152. (PMID: 35058631); Science. 2016 Oct 28;354(6311):. (PMID: 27789812); Nat Immunol. 2021 Feb;22(2):205-215. (PMID: 33398183); BMC Bioinformatics. 2009 May 27;10:161. (PMID: 19473525); PLoS Biol. 2015 Dec 01;13(12):e1002309. (PMID: 26625127); Cell Metab. 2020 Dec 1;32(6):1063-1075.e7. (PMID: 33264598); Nature. 2020 Jan;577(7788):115-120. (PMID: 31853067); iScience. 2020 Jan 24;23(1):100759. (PMID: 31887663); Cell Metab. 2020 Feb 4;31(2):250-266.e9. (PMID: 32023446); Cell. 2017 May 4;169(4):570-586. (PMID: 28475890); Nat Rev Immunol. 2016 Sep;16(9):553-65. (PMID: 27396447); Cell. 2013 Jun 6;153(6):1239-51. (PMID: 23746840); Nat Metab. 2020 Feb;2(2):127-129. (PMID: 32694689); Nat Protoc. 2021 Sep;16(9):4494-4521. (PMID: 34349284); Nat Immunol. 2014 Apr;15(4):323-32. (PMID: 24562310); Cell Metab. 2021 Jun 1;33(6):1248-1263.e9. (PMID: 33651980); BMC Bioinformatics. 2016 Nov 25;17(1):485. (PMID: 27887574); Science. 2021 Jan 22;371(6527):405-410. (PMID: 33479154); J Immunol. 2005 Apr 15;174(8):4670-7. (PMID: 15814691); Cell Metab. 2014 Jul 1;20(1):61-72. (PMID: 24930970); Immunity. 2020 May 19;52(5):825-841.e8. (PMID: 32396847); Trends Cell Biol. 2019 Nov;29(11):854-861. (PMID: 31623927); Immunity. 2015 Jan 20;42(1):41-54. (PMID: 25607458); Cell Rep. 2020 Dec 15;33(11):108500. (PMID: 33326785); Nat Immunol. 2019 Jul;20(7):890-901. (PMID: 31209400); Nature. 2017 Nov 2;551(7678):115-118. (PMID: 29045397); J Biol Chem. 2017 Apr 28;292(17):7189-7207. (PMID: 28270511); Cell. 2018 May 3;173(4):822-837. (PMID: 29727671); Annu Rev Immunol. 2007;25:171-92. (PMID: 17129182); Immunity. 2014 Aug 21;41(2):325-38. (PMID: 25148027); Cell Metab. 2020 Oct 6;32(4):676-688.e4. (PMID: 32791100); Cell Rep. 2019 Sep 17;28(12):3011-3021.e4. (PMID: 31533027); Nat Biotechnol. 2021 Feb;39(2):186-197. (PMID: 32868913); Nat Immunol. 2004 Aug;5(8):809-17. (PMID: 15247915); Immunity. 2011 Dec 23;35(6):871-82. (PMID: 22195744); Cell. 2017 Oct 5;171(2):358-371.e9. (PMID: 28985563); Mol Cell. 2021 Feb 18;81(4):691-707.e6. (PMID: 33382985); Nat Metab. 2020 Jul;2(7):635-647. (PMID: 32694789); Sci Immunol. 2020 Jul 3;5(49):. (PMID: 32620560); Cell. 2016 Feb 11;164(4):681-94. (PMID: 26853473); Immunity. 2016 Jun 21;44(6):1312-24. (PMID: 27212436) |
| Grant Information: | R00 CA237724 United States CA NCI NIH HHS; R01 AI165722 United States AI NIAID NIH HHS; R35 CA220449 United States CA NCI NIH HHS; T32 CA251066 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: (13)C tracing; T cells; TCA cycle; immunometabolism; lactate; metabolic programming; metabolomics |
| Substance Nomenclature: | 7440-44-0 (Carbon); IY9XDZ35W2 (Glucose); 33X04XA5AT (Lactic Acid); 0 (Nutrients) |
| Entry Date(s): | Date Created: 20220818 Date Completed: 20220909 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10068808 |
| DOI: | 10.1016/j.cmet.2022.07.012 |
| PMID: | 35981545 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't