Emerging Concepts of T Cell Metabolism As a Target of Immunotherapy

Overview

Journal Nat Immunol

Date 2016 Mar 23

PMID 27002844

Citations 183

Authors

Chih-Hao Chang

Erika L Pearce

Affiliations

Soon will be listed here.

Abstract

T cells have a pivotal protective role in defense against infection and cancer but also are instrumental in the development of many autoimmune diseases. The regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation, and manipulating metabolic pathways in these cells can alter their function and longevity. While the importance of T cell metabolic remodeling in different physiological settings is not fully understood, there is a growing realization that inappropriate metabolic remodeling underlies many aberrant immune responses and that manipulating cellular metabolism can beneficially enhance or temper immunity. Here we comment on the basic metabolic pathways in T cells, followed by a discussion on up-to-date findings about the relationship between metabolism and T cell function and longevity. Furthermore, we expand on potential approaches and applications in which T cells might be manipulated by the reprogramming of metabolic pathways for therapeutic purposes.

Citing Articles

Impact of immune cell metabolism on membranous nephropathy and prospective therapy.

Duan X, Lv X, Wang X, Zhang Y, Hu Y, Li H Commun Biol. 2025; 8(1):405.

PMID: 40065158 PMC: 11893770. DOI: 10.1038/s42003-025-07816-3.

Immunometabolism of Liver Xenotransplantation and Prospective Solutions.

Deng S, Zhang Y, Shen S, Li C, Qin C Adv Sci (Weinh). 2025; 12(9):e2407610.

PMID: 39912334 PMC: 11884532. DOI: 10.1002/advs.202407610.

Neoantigen mRNA vaccines and AA receptor antagonism: A strategy to enhance T cell immunity.

Imani S, Jabbarzadeh Kaboli P, Babaeizad A, Maghsoudloo M Hum Vaccin Immunother. 2025; 21(1):2458936.

PMID: 39882781 PMC: 11784654. DOI: 10.1080/21645515.2025.2458936.

Metabolic Signaling in the Tumor Microenvironment.

Clay R, Li K, Jin L Cancers (Basel). 2025; 17(1.

PMID: 39796781 PMC: 11719658. DOI: 10.3390/cancers17010155.

Role of T cell metabolism in brain tumor development: a genetic and metabolic approach.

Yang B, Li Z, Li P, Liang B, Liu Y, Feng E BMC Neurol. 2025; 25(1):12.

PMID: 39780065 PMC: 11708232. DOI: 10.1186/s12883-024-04015-1.

References

Wang R, Dillon C, Shi L, Milasta S, Carter R, Finkelstein D . The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011; 35(6):871-82. PMC: 3248798. DOI: 10.1016/j.immuni.2011.09.021. View

Wang Y, Wang X, Subjeck J, Shrikant P, Kim H . Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br J Cancer. 2011; 104(4):643-52. PMC: 3049595. DOI: 10.1038/bjc.2011.15. View

Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K . De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 2014; 20(11):1327-33. DOI: 10.1038/nm.3704. View

Munn D, Sharma M, Baban B, Harding H, Zhang Y, Ron D . GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005; 22(5):633-42. DOI: 10.1016/j.immuni.2005.03.013. View

Gerriets V, Kishton R, Nichols A, Macintyre A, Inoue M, Ilkayeva O . Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest. 2014; 125(1):194-207. PMC: 4382238. DOI: 10.1172/JCI76012. View

Sukumar M, Liu J, Mehta G, Patel S, Roychoudhuri R, Crompton J . Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. Cell Metab. 2015; 23(1):63-76. PMC: 4747432. DOI: 10.1016/j.cmet.2015.11.002. View

Opitz C, Litzenburger U, Sahm F, Ott M, Tritschler I, Trump S . An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011; 478(7368):197-203. DOI: 10.1038/nature10491. View

OSullivan D, Pearce E . Targeting T cell metabolism for therapy. Trends Immunol. 2015; 36(2):71-80. PMC: 4323623. DOI: 10.1016/j.it.2014.12.004. View

Blagih J, Coulombe F, Vincent E, Dupuy F, Galicia-Vazquez G, Yurchenko E . The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015; 42(1):41-54. DOI: 10.1016/j.immuni.2014.12.030. View

10.

Rolf J, Zarrouk M, Finlay D, Foretz M, Viollet B, Cantrell D . AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol. 2013; 43(4):889-96. PMC: 3734624. DOI: 10.1002/eji.201243008. View

11.

Cham C, Gajewski T . Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol. 2005; 174(8):4670-7. DOI: 10.4049/jimmunol.174.8.4670. View

12.

Buck M, OSullivan D, Pearce E . T cell metabolism drives immunity. J Exp Med. 2015; 212(9):1345-60. PMC: 4548052. DOI: 10.1084/jem.20151159. View

13.

Chaoul N, Fayolle C, Desrues B, Oberkampf M, Tang A, Ladant D . Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication. Cancer Res. 2015; 75(16):3279-91. DOI: 10.1158/0008-5472.CAN-15-0454. View

14.

van der Windt G, Everts B, Chang C, Curtis J, Freitas T, Amiel E . Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2011; 36(1):68-78. PMC: 3269311. DOI: 10.1016/j.immuni.2011.12.007. View

15.

Cui G, Staron M, Gray S, Ho P, Amezquita R, Wu J . IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity. Cell. 2015; 161(4):750-61. PMC: 4704440. DOI: 10.1016/j.cell.2015.03.021. View

16.

Fraser K, Schenkel J, Jameson S, Vezys V, Masopust D . Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity. 2013; 39(1):171-83. PMC: 3979587. DOI: 10.1016/j.immuni.2013.07.003. View

17.

Lee J, Walsh M, Hoehn K, James D, Wherry E, Choi Y . Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol. 2014; 192(7):3190-9. PMC: 3965631. DOI: 10.4049/jimmunol.1302985. View

18.

Mezrich J, Fechner J, Zhang X, Johnson B, Burlingham W, Bradfield C . An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010; 185(6):3190-8. PMC: 2952546. DOI: 10.4049/jimmunol.0903670. View

19.

Pearce E, Walsh M, Cejas P, Harms G, Shen H, Wang L . Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009; 460(7251):103-7. PMC: 2803086. DOI: 10.1038/nature08097. View

20.

MacIver N, Blagih J, Saucillo D, Tonelli L, Griss T, Rathmell J . The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol. 2011; 187(8):4187-98. PMC: 3206094. DOI: 10.4049/jimmunol.1100367. View