Metabolic Signaling in T Cells

Overview

Journal Cell Res

Specialty Cell Biology

Date 2020 Jul 26

PMID 32709897

Citations 150

Authors

Justin A Shyer

Richard A Flavell

Will Bailis

Affiliations

Soon will be listed here.

Abstract

The maintenance of organismal homeostasis requires partitioning and transport of biochemical molecules between organ systems, their composite cells, and subcellular organelles. Although transcriptional programming undeniably defines the functional state of cells and tissues, underlying biochemical networks are intricately intertwined with transcriptional, translational, and post-translational regulation. Studies of the metabolic regulation of immunity have elegantly illustrated this phenomenon. The cells of the immune system interface with a diverse set of environmental conditions. Circulating immune cells perfuse peripheral organs in the blood and lymph, patrolling for pathogen invasion. Resident immune cells remain in tissues and play more newly appreciated roles in tissue homeostasis and immunity. Each of these cell populations interacts with unique and dynamic tissue environments, which vary greatly in biochemical composition. Furthermore, the effector response of immune cells to a diverse set of activating cues requires unique cellular adaptations to supply the requisite biochemical landscape. In this review, we examine the role of spatial partitioning of metabolic processes in immune function. We focus on studies of lymphocyte metabolism, with reference to the greater immunometabolism literature when appropriate to illustrate this concept.

Citing Articles

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References

Bensinger S, Bradley M, Joseph S, Zelcer N, Janssen E, Hausner M . LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008; 134(1):97-111. PMC: 2626438. DOI: 10.1016/j.cell.2008.04.052. View

Beier U, Wang L, Han R, Akimova T, Liu Y, Hancock W . Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci Signal. 2012; 5(229):ra45. PMC: 3603571. DOI: 10.1126/scisignal.2002873. View

Liu X, Karnell J, Yin B, Zhang R, Zhang J, Li P . Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice. J Clin Invest. 2010; 120(7):2497-507. PMC: 2898609. DOI: 10.1172/JCI42382. View

Dang E, Barbi J, Yang H, Jinasena D, Yu H, Zheng Y . Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011; 146(5):772-84. PMC: 3387678. DOI: 10.1016/j.cell.2011.07.033. View

Bailis W, Shyer J, Zhao J, Garcia Canaveras J, Al Khazal F, Qu R . Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature. 2019; 571(7765):403-407. PMC: 6939459. DOI: 10.1038/s41586-019-1311-3. View

Lin W, Chen W, Liu W, Xu Z, Zhang L . Sirtuin4 suppresses the anti-neuroinflammatory activity of infiltrating regulatory T cells in the traumatically injured spinal cord. Immunology. 2019; 158(4):362-374. PMC: 6856927. DOI: 10.1111/imm.13123. View

Saxton R, Knockenhauer K, Wolfson R, Chantranupong L, Pacold M, Wang T . Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2015; 351(6268):53-8. PMC: 4698039. DOI: 10.1126/science.aad2087. View

Kim S, Yang J, Lee K, Oh K, Gi M, Kim J . Bacillus subtilis-specific poly-gamma-glutamic acid regulates development pathways of naive CD4(+) T cells through antigen-presenting cell-dependent and -independent mechanisms. Int Immunol. 2009; 21(8):977-90. DOI: 10.1093/intimm/dxp065. View

Kearse K, Hart G . Lymphocyte activation induces rapid changes in nuclear and cytoplasmic glycoproteins. Proc Natl Acad Sci U S A. 1991; 88(5):1701-5. PMC: 51092. DOI: 10.1073/pnas.88.5.1701. View

10.

Herold M, Breuer J, Hucke S, Knolle P, Schwab N, Wiendl H . Liver X receptor activation promotes differentiation of regulatory T cells. PLoS One. 2017; 12(9):e0184985. PMC: 5604992. DOI: 10.1371/journal.pone.0184985. View

11.

De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C . Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. 2015; 16(11):1174-84. PMC: 4868085. DOI: 10.1038/ni.3269. View

12.

Saxton R, Chantranupong L, Knockenhauer K, Schwartz T, Sabatini D . Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature. 2016; 536(7615):229-33. PMC: 4988899. DOI: 10.1038/nature19079. View

13.

Waickman A, Powell J . mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev. 2012; 249(1):43-58. PMC: 3419491. DOI: 10.1111/j.1600-065X.2012.01152.x. View

14.

Dustin M, Olszowy M, Holdorf A, Li J, Bromley S, Desai N . A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell. 1998; 94(5):667-77. DOI: 10.1016/s0092-8674(00)81608-6. View

15.

Marchingo J, Sinclair L, Howden A, Cantrell D . Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation. Elife. 2020; 9. PMC: 7056270. DOI: 10.7554/eLife.53725. View

16.

Previte D, OConnor E, Novak E, Martins C, Mollen K, Piganelli J . Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLoS One. 2017; 12(4):e0175549. PMC: 5398529. DOI: 10.1371/journal.pone.0175549. View

17.

Osman N, Turner H, Lucas S, Reif K, Cantrell D . The protein interactions of the immunoglobulin receptor family tyrosine-based activation motifs present in the T cell receptor zeta subunits and the CD3 gamma, delta and epsilon chains. Eur J Immunol. 1996; 26(5):1063-8. DOI: 10.1002/eji.1830260516. View

18.

Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell L . PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015; 6:6692. PMC: 4389235. DOI: 10.1038/ncomms7692. View

19.

Harder T, Kuhn M . Selective accumulation of raft-associated membrane protein LAT in T cell receptor signaling assemblies. J Cell Biol. 2000; 151(2):199-208. PMC: 2192654. DOI: 10.1083/jcb.151.2.199. View

20.

Kim E, Goraksha-Hicks P, Li L, Neufeld T, Guan K . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10(8):935-45. PMC: 2711503. DOI: 10.1038/ncb1753. View