Metabolic Regulation of T Cell Differentiation and Function

Overview

Journal Mol Immunol

Specialties Allergy & Immunology
Molecular Biology

Date 2015 Aug 17

PMID 26277275

Citations 24

Authors

Benjamin V Park

Fan Pan

Affiliations

Soon will be listed here.

Abstract

Upon encountering pathogens, T cells mount immune responses by proliferating, increasing cellular mass and differentiating. These cellular changes impose significant energetic challenges on T cells. It was believed that TCR and cytokine-mediated signaling are dominant dictators of T cell-mediated immune responses. Recently, it was recognized that T cells utilize metabolic transporters and metabolic sensors that allow them to rapidly respond to nutrient-limiting inflammatory environments. Metabolic sensors allow T cells to find a balance between energy consumption (anabolic metabolism) and production (catabolic metabolism) in order to mount effective immune responses. Also, metabolic regulators interact with cytokine-dependent transcriptional regulators, suggesting a more integrative and advanced model of T cell activation and differentiation. In this review, we will discuss recent discoveries regarding the roles of metabolic regulators in effector and memory T cell development and their interaction with canonical transcription factors.

Citing Articles

Mesenchymal Stem Cell-Derived Exosomes: Emerging as a Promising Cell-Free Therapeutic Strategy for Autoimmune Hepatitis.

Wu L, Zhang L, Huang M, Wu Y, Jin S, Zhang Y Biomolecules. 2024; 14(11).

PMID: 39595530 PMC: 11592114. DOI: 10.3390/biom14111353.

Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice.

Niri T, Inoue S, Akazawa S, Nishikido S, Miwa M, Kobayashi M Clin Exp Immunol. 2024; 219(1).

PMID: 39432837 PMC: 11773818. DOI: 10.1093/cei/uxae093.

Pyroptosis of oral keratinocyte contributes to energy metabolic reprogramming of T cells in oral lichen planus via OPA1-mediated mitochondrial fusion.

Yang Z, Deng M, Ren L, Fan Z, Yang S, Liu S Cell Death Discov. 2024; 10(1):408.

PMID: 39289349 PMC: 11408637. DOI: 10.1038/s41420-024-02174-1.

Immunometabolic alteration of CD4 T cells in the pathogenesis of primary Sjögren's syndrome.

Chen Y, Luo X, Deng C, Zhao L, Gao H, Zhou J Clin Exp Med. 2024; 24(1):163.

PMID: 39039306 PMC: 11263433. DOI: 10.1007/s10238-024-01429-6.

GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.

Shi Y, Kotchetkov I, Dobrin A, Hanina S, Rajasekhar V, Healey J Mol Ther. 2024; 32(7):2393-2405.

PMID: 38720457 PMC: 11286825. DOI: 10.1016/j.ymthe.2024.05.006.

References

Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L . Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol. 2006; 177(8):4962-5. DOI: 10.4049/jimmunol.177.8.4962. View

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

Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B . Metformin: from mechanisms of action to therapies. Cell Metab. 2014; 20(6):953-66. DOI: 10.1016/j.cmet.2014.09.018. View

Clambey E, McNamee E, Westrich J, Glover L, Campbell E, Jedlicka P . Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A. 2012; 109(41):E2784-93. PMC: 3478644. DOI: 10.1073/pnas.1202366109. View

Finlay D, Rosenzweig E, Sinclair L, Feijoo-Carnero C, Hukelmann J, Rolf J . PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med. 2012; 209(13):2441-53. PMC: 3526360. DOI: 10.1084/jem.20112607. 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

Warburg O . On the origin of cancer cells. Science. 1956; 123(3191):309-14. DOI: 10.1126/science.123.3191.309. View

Warburg O . On respiratory impairment in cancer cells. Science. 1956; 124(3215):269-70. View

Tzachanis D, Freeman G, Hirano N, van Puijenbroek A, Delfs M, Berezovskaya A . Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol. 2001; 2(12):1174-82. DOI: 10.1038/ni730. View

10.

Zheng Y, Delgoffe G, Meyer C, Chan W, Powell J . Anergic T cells are metabolically anergic. J Immunol. 2009; 183(10):6095-101. PMC: 2884282. DOI: 10.4049/jimmunol.0803510. View

11.

Semenza G . HIF-1 and human disease: one highly involved factor. Genes Dev. 2000; 14(16):1983-91. View

12.

Hatzivassiliou G, Zhao F, Bauer D, Andreadis C, Shaw A, Dhanak D . ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005; 8(4):311-21. DOI: 10.1016/j.ccr.2005.09.008. View

13.

Yusuf I, Fruman D . Regulation of quiescence in lymphocytes. Trends Immunol. 2003; 24(7):380-6. DOI: 10.1016/s1471-4906(03)00141-8. View

14.

Hamilton S, Jameson S . CD8 T cell quiescence revisited. Trends Immunol. 2012; 33(5):224-30. PMC: 3348359. DOI: 10.1016/j.it.2012.01.007. View

15.

Doedens A, Phan A, Stradner M, Fujimoto J, Nguyen J, Yang E . Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol. 2013; 14(11):1173-82. PMC: 3977965. DOI: 10.1038/ni.2714. View

16.

Newsholme P . Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?. J Nutr. 2001; 131(9 Suppl):2515S-22S; discussion 2523S-4S. DOI: 10.1093/jn/131.9.2515S. View

17.

Pan F, Barbi J, Pardoll D . Hypoxia-inducible factor 1: A link between metabolism and T cell differentiation and a potential therapeutic target. Oncoimmunology. 2012; 1(4):510-515. PMC: 3382896. DOI: 10.4161/onci.19457. View

18.

Heikamp E, Patel C, Collins S, Waickman A, Oh M, Sun I . The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol. 2014; 15(5):457-64. PMC: 4267697. DOI: 10.1038/ni.2867. View

19.

Nath N, Khan M, Rattan R, Mangalam A, Makkar R, de Meester C . Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity. Biochem Biophys Res Commun. 2009; 386(1):16-20. PMC: 2976596. DOI: 10.1016/j.bbrc.2009.05.106. View

20.

Nath N, Giri S, Prasad R, Salem M, Singh A, Singh I . 5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J Immunol. 2005; 175(1):566-74. DOI: 10.4049/jimmunol.175.1.566. View