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Metabolic Choice Tunes Foxp3+ Regulatory T Cell Function

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Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1278)

Abstract

Metabolic programs and dynamic nutrient signaling can direct cell biological function. Cellular metabolism and biological function are coordinated to cell activity. Regulatory T cells (Foxp3+ Tregs) expressing the key transcription factor FOXP3 play critical roles in the maintenance of immune tolerance and in the control of immune homeostasis. A bundle of data demonstrated that Foxp3+ Tregs were influenced and regulated by Toll-cell receptor (TCR) and costimulatory signals, cytokine conditions and metabolic changes, including metabolites, etc. In this context, Foxp3+ Tregs are impacted by different environmental conditions and metabolic differences associated with diverse transcriptional patterns, which, in turn, display a high degree of plasticity and tissue specificity. During the past decades, significant progresses have been made in understanding the correlation between metabolic changes and manipulation of Foxp3+ Treg function. Taken together, this chapter aims to summarize the important advances in the fields, decipher what metabolic ways are involved in Foxp3+ Tregs, and how metabolism modulates Foxp3 expression, stability, and suppressive functions, which may provide a potential pace on lightening up Foxp3+ Treg-mediated immune functions.

Keywords

Metabolism Foxp3+ Tregs Immunomodulatory functions 

Abbreviations

3-HAA

3-hydroxyanthranilic acid

AhR

Aryl hydrocarbon receptor

BCAAs

Branched-chain amino acids

CBM

CARMA1-BCL10-MALT1

FAO

Fatty acid oxidation

GlcNAc

N-acetylglucosamine

GLS

Glutaminase

HDAC

Histone deacetylase

IDO

Indoleamine 2,3-dioxygenase

LNAA

Large neutral amino acids

MS

Multiple sclerosis

NO

Nitric oxide

OXPHOS

Oxidative phosphorylation

PARP1

Poly (ADP-ribose) polymerase 1

PIM1

Proto-oncogene serine/threonine-protein kinase

TCR

Toll-cell receptor

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References

  1. Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293 e1287.  https://doi.org/10.1016/j.cmet.2016.12.018CrossRefPubMedPubMedCentralGoogle Scholar
  2. Araujo L, Khim P, Mkhikian H, Mortales C-L, Demetriou M (2017) Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife 6:e21330.  https://doi.org/10.7554/eLife.21330CrossRefPubMedPubMedCentralGoogle Scholar
  3. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455.  https://doi.org/10.1038/nature12726CrossRefPubMedPubMedCentralGoogle Scholar
  4. Beier UH, Wang L, Bhatti TR, Liu Y, Han R, Ge G, Hancock WW (2011) Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol Cell Biol 31(5):1022–1029.  https://doi.org/10.1128/MCB.01206-10CrossRefPubMedPubMedCentralGoogle Scholar
  5. Buck Michael D, O’Sullivan D, Klein Geltink Ramon I, Curtis Jonathan D, Chang C-H, Sanin David E, Qiu J, Kretz O, Braas D, van der Windt Gerritje JW, Chen Q, Huang Stanley C-C, O’Neill Christina M, Edelson Brian T, Pearce Edward J, Sesaki H, Huber Tobias B, Rambold Angelika S, Pearce Erika L (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166(1):63–76.  https://doi.org/10.1016/j.cell.2016.05.035CrossRefPubMedPubMedCentralGoogle Scholar
  6. Carbone F, De Rosa V, Carrieri PB, Montella S, Bruzzese D, Porcellini A, Procaccini C, La Cava A, Matarese G (2013) Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med 20(1):69–74.  https://doi.org/10.1038/nm.3411CrossRefPubMedGoogle Scholar
  7. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA (2010) Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185(2):1037–1044.  https://doi.org/10.4049/jimmunol.0903586CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chai M, Jiang M, Vergnes L, Fu X, de Barros SC, Doan NB, Huang W, Chu J, Jiao J, Herschman H, Crooks GM, Reue K, Huang J (2019) Stimulation of hair growth by small molecules that activate autophagy. Cell Rep 27(12):3413–3421.e3413.  https://doi.org/10.1016/j.celrep.2019.05.070CrossRefPubMedGoogle Scholar
  9. Chen Z, Barbi J, Bu S, Yang H-Y, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park Benjamin V, Pan Z, Zhang J, Dang E, Li Z, Wang H, Luo W, Li L, Semenza Gregg L, Zheng S-G, Loser K, Tsun A, Greene Mark I, Pardoll Drew M, Pan F, Li B (2013) The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39(2):272–285.  https://doi.org/10.1016/j.immuni.2013.08.006CrossRefPubMedGoogle Scholar
  10. Chen X, Su W, Wan T, Yu J, Zhu W, Tang F, Liu G, Olsen N, Liang D, Zheng SG (2017) Sodium butyrate regulates Th17/Treg cell balance to ameliorate uveitis via the Nrf2/HO-1 pathway. Biochem Pharmacol 142:111–119.  https://doi.org/10.1016/j.bcp.2017.06.136CrossRefPubMedGoogle Scholar
  11. Chen Y, Colello J, Jarjour W, Zheng SG (2019) Cellular metabolic regulation in the differentiation and function of regulatory T cells. Cells 8(2):188.  https://doi.org/10.3390/cells8020188CrossRefPubMedCentralGoogle Scholar
  12. Chunder N, Wang L, Chen C, Hancock WW, Wells AD (2012) Cyclin-dependent kinase 2 controls peripheral immune tolerance. J Immunol 189(12):5659–5666.  https://doi.org/10.4049/jimmunol.1202313CrossRefPubMedPubMedCentralGoogle Scholar
  13. Comito G, Iscaro A, Bacci M, Morandi A, Ippolito L, Parri M, Montagnani I, Raspollini MR, Serni S, Simeoni L, Giannoni E, Chiarugi P (2019) Lactate modulates CD4(+) T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene 38(19):3681–3695.  https://doi.org/10.1038/s41388-019-0688-7CrossRefPubMedGoogle Scholar
  14. Daley SR, Coakley KM, Hu DY, Randall KL, Jenne CN, Limnander A, Myers DR, Polakos NK, Enders A, Roots C, Balakishnan B, Miosge LA, Sjollema G, Bertram EM, Field MA, Shao Y, Andrews TD, Whittle B, Barnes SW, Walker JR, Cyster JG, Goodnow CC, Roose JP (2013) Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies. eLife 2:e01020.  https://doi.org/10.7554/eLife.01020CrossRefPubMedPubMedCentralGoogle Scholar
  15. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784.  https://doi.org/10.1016/j.cell.2011.07.033CrossRefPubMedPubMedCentralGoogle Scholar
  16. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM (2007) Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 178(7):4022–4026.  https://doi.org/10.4049/jimmunol.178.7.4022CrossRefPubMedGoogle Scholar
  17. De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, Romano A, De Simone S, Procaccini C, La Rocca C, Carrieri PB, Maniscalco GT, Salvetti M, Buscarinu MC, Franzese A, Mozzillo E, La Cava A, Matarese G (2015) Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol 16(11):1174–1184.  https://doi.org/10.1038/ni.3269CrossRefPubMedPubMedCentralGoogle Scholar
  18. de Zoeten EF, Wang L, Sai H, Dillmann WH, Hancock WW (2010) Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice. Gastroenterology 138(2):583–594.  https://doi.org/10.1053/j.gastro.2009.10.037CrossRefPubMedGoogle Scholar
  19. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30(6):832–844.  https://doi.org/10.1016/j.immuni.2009.04.014CrossRefPubMedPubMedCentralGoogle Scholar
  20. Fu Z, Ye J, Dean JW, Bostick JW, Weinberg SE, Xiong L, Oliff KN, Chen ZE, Avram D, Chandel NS, Zhou L (2019) Requirement of mitochondrial transcription factor A in tissue-resident regulatory T cell maintenance and function. Cell Rep 28(1):159–171.e154.  https://doi.org/10.1016/j.celrep.2019.06.024CrossRefPubMedPubMedCentralGoogle Scholar
  21. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450.  https://doi.org/10.1038/nature12721CrossRefGoogle Scholar
  22. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, Zamboni N, Sallusto F, Lanzavecchia A (2016) L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167(3):829–842 e813.  https://doi.org/10.1016/j.cell.2016.09.031CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, Winter PS, Liu X, Priyadharshini B, Slawinska ME, Haeberli L, Huck C, Turka LA, Wood KC, Hale LP, Smith PA, Schneider MA, MacIver NJ, Locasale JW, Newgard CB, Shinohara ML, Rathmell JC (2015) Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest 125(1):194–207.  https://doi.org/10.1172/JCI76012CrossRefPubMedGoogle Scholar
  24. Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, Warmoes MO, de Cubas AA, MacIver NJ, Locasale JW, Turka LA, Wells AD, Rathmell JC (2016) Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol 17(12):1459–1466.  https://doi.org/10.1038/ni.3577CrossRefPubMedPubMedCentralGoogle Scholar
  25. Grohmann U, Bronte V (2010) Control of immune response by amino acid metabolism. Immunol Rev 236:243–264.  https://doi.org/10.1111/j.1600-065X.2010.00915.xCrossRefPubMedGoogle Scholar
  26. Grzes KM, Field CS, Pearce EJ (2017) Treg cells survive and thrive in inhospitable environments. Cell Metab 25(6):1213–1215.  https://doi.org/10.1016/j.cmet.2017.05.012CrossRefPubMedGoogle Scholar
  27. Hawse WF, Cattley RT, Wendell SG (2019) Cutting edge: TCR signal strength regulates acetyl-CoA metabolism via AKT. J Immunol 203(11):2771–2775.  https://doi.org/10.4049/jimmunol.1900749CrossRefPubMedGoogle Scholar
  28. He N, Fan W, Henriquez B, Yu RT, Atkins AR, Liddle C, Zheng Y, Downes M, Evans RM (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A 114(47):12542–12547.  https://doi.org/10.1073/pnas.1715363114CrossRefPubMedPubMedCentralGoogle Scholar
  29. Horwitz DA, Zheng SG, Gray JD (2008) Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol 29(9):429–435.  https://doi.org/10.1016/j.it.2008.06.005CrossRefPubMedGoogle Scholar
  30. Huang F, Chen M, Chen W, Gu J, Yuan J, Xue Y, Dang J, Su W, Wang J, Zadeh HH, He X, Rong L, Olsen N, Zheng SG (2017) Human gingiva-derived mesenchymal stem cells inhibit xeno-graft-versus-host disease via CD39-CD73-adenosine and IDO signals. Front Immunol 8:68.  https://doi.org/10.3389/fimmu.2017.00068CrossRefPubMedPubMedCentralGoogle Scholar
  31. Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16(2):188–196.  https://doi.org/10.1038/ni.3077CrossRefPubMedPubMedCentralGoogle Scholar
  32. Ikeda K, Kinoshita M, Kayama H, Nagamori S, Kongpracha P, Umemoto E, Okumura R, Kurakawa T, Murakami M, Mikami N, Shintani Y, Ueno S, Andou A, Ito M, Tsumura H, Yasutomo K, Ozono K, Takashima S, Sakaguchi S, Kanai Y, Takeda K (2017) Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep 21(7):1824–1838.  https://doi.org/10.1016/j.celrep.2017.10.082CrossRefPubMedGoogle Scholar
  33. Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A, Contreras DC, Maseda D, Liberti MV, Paz K, Kishton RJ, Johnson ME, de Cubas AA, Wu P, Li G, Zhang Y, Newcomb DC, Wells AD, Restifo NP, Rathmell WK, Locasale JW, Davila ML, Blazar BR, Rathmell JC (2018) Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell 175(7):1780–1795 e1719.  https://doi.org/10.1016/j.cell.2018.10.001CrossRefPubMedPubMedCentralGoogle Scholar
  34. Jorg VL et al (2010) Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Immunology 115(5):965–974.  https://doi.org/10.1182/blood-2009-02-207118CrossRefGoogle Scholar
  35. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564.  https://doi.org/10.1146/annurev.immunol.25.022106.141623CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH (2007) Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 179(6):3724–3733.  https://doi.org/10.4049/jimmunol.179.6.3724CrossRefPubMedGoogle Scholar
  37. Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM (2017) Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47(5):875–889.e810.  https://doi.org/10.1016/j.immuni.2017.10.017CrossRefPubMedPubMedCentralGoogle Scholar
  38. Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G, Oburoglu L, Mongellaz C, Floess S, Fritz V, Matias MI, Yong C, Surh N, Marie JC, Huehn J, Zimmermann V, Kinet S, Dardalhon V, Taylor N (2015) Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal 8(396):ra97.  https://doi.org/10.1126/scisignal.aab2610CrossRefPubMedGoogle Scholar
  39. Kong N, Lan Q, Chen M, Wang J, Shi W, Horwitz DA, Quesniaux V, Ryffel B, Liu Z, Brand D, Zou H, Zheng SG (2012a) Antigen-specific transforming growth factor beta-induced Treg cells, but not natural Treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominance. Arthritis Rheum 64(8):2548–2558.  https://doi.org/10.1002/art.34513CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kong N, Lan Q, Su W, Chen M, Wang J, Yang Z, Park R, Dagliyan G, Conti PS, Brand D, Liu Z, Stohl W, Zou H, Zheng SG (2012b) Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells. Ann Rheum Dis 71(9):1567–1572.  https://doi.org/10.1136/annrheumdis-2011-201052CrossRefPubMedPubMedCentralGoogle Scholar
  41. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, Armand P, Cutler C, Ho VT, Treister NS, Bienfang DC, Prasad S, Tzachanis D, Joyce RM, Avigan DE, Antin JH, Ritz J, Soiffer RJ (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 365(22):2055–2066.  https://doi.org/10.1056/NEJMoa1108188CrossRefPubMedPubMedCentralGoogle Scholar
  42. Krause D, Suh HS, Tarassishin L, Cui QL, Durafourt BA, Choi N, Bauman A, Cosenza-Nashat M, Antel JP, Zhao ML, Lee SC (2011) The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1. Am J Pathol 179(3):1360–1372.  https://doi.org/10.1016/j.ajpath.2011.05.048CrossRefPubMedPubMedCentralGoogle Scholar
  43. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL (2002) Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107(4):452–460.  https://doi.org/10.1046/j.1365-2567.2002.01526.xCrossRefPubMedPubMedCentralGoogle Scholar
  44. Li B, Greene MI (2008) Special regulatory T-cell review: FOXP3 biochemistry in regulatory T cells--how diverse signals regulate suppression. Immunology 123(1):17–19.  https://doi.org/10.1111/j.1365-2567.2007.02774.xCrossRefPubMedPubMedCentralGoogle Scholar
  45. Li B, Samanta A, Song X, Iacono KT, Bembas K, Tao R, Basu S, Riley JL, Hancock WW, Shen Y, Saouaf SJ, Greene MI (2007) FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci U S A 104(11):4571–4576.  https://doi.org/10.1073/pnas.0700298104CrossRefPubMedPubMedCentralGoogle Scholar
  46. Li Z, Lin F, Zhuo C, Deng G, Chen Z, Yin S, Gao Z, Piccioni M, Tsun A, Cai S, Zheng SG, Zhang Y, Li B (2014) PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J Biol Chem 289(39):26872–26881.  https://doi.org/10.1074/jbc.M114.586651CrossRefPubMedPubMedCentralGoogle Scholar
  47. Li Y, Lu Y, Wang S, Han Z, Zhu F, Ni Y, Liang R, Zhang Y, Leng Q, Wei G, Shi G, Zhu R, Li D, Wang H, Zheng SG, Xu H, Tsun A, Li B (2016) USP21 prevents the generation of T-helper-1-like Treg cells. Nat Commun 7:13559.  https://doi.org/10.1038/ncomms13559CrossRefPubMedPubMedCentralGoogle Scholar
  48. Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, Gao A, Huang L, Hsueh EC, Ford DA, Hoft DF, Peng G (2019) TLR8-mediated metabolic control of human Treg function: a mechanistic target for cancer immunotherapy. Cell Metab 29(1):103–123.e105.  https://doi.org/10.1016/j.cmet.2018.09.020CrossRefPubMedGoogle Scholar
  49. Lin F, Luo X, Tsun A, Li Z, Li D, Li B (2015) Kaempferol enhances the suppressive function of Treg cells by inhibiting FOXP3 phosphorylation. Int Immunopharmacol 28(2):859–865.  https://doi.org/10.1016/j.intimp.2015.03.044CrossRefPubMedGoogle Scholar
  50. Liu Y, Wang L, Predina J, Han R, Beier UH, Wang L-CS, Kapoor V, Bhatti TR, Akimova T, Singhal S, Brindle PK, Cole PA, Albelda SM, Hancock WW (2013) Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity. Nat Med 19(9):1173–1177.  https://doi.org/10.1038/nm.3286CrossRefPubMedPubMedCentralGoogle Scholar
  51. Lu L, Ma J, Li Z, Lan Q, Chen M, Liu Y, Xia Z, Wang J, Han Y, Shi W, Quesniaux V, Ryffel B, Brand D, Li B, Liu Z, Zheng SG (2011) All-trans retinoic acid promotes TGF-beta-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus. PLoS One 6(9):e24590.  https://doi.org/10.1371/journal.pone.0024590CrossRefPubMedPubMedCentralGoogle Scholar
  52. Lu L, Lan Q, Li Z, Zhou X, Gu J, Li Q, Wang J, Chen M, Liu Y, Shen Y, Brand DD, Ryffel B, Horwitz DA, Quismorio FP, Liu Z, Li B, Olsen NJ, Zheng SG (2014) Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A 111(33):E3432–E3440.  https://doi.org/10.1073/pnas.1408780111CrossRefPubMedPubMedCentralGoogle Scholar
  53. Luengo A, Gui DY, Vander Heiden MG (2017) Targeting metabolism for cancer therapy. Cell Chem Biol 24(9):1161–1180.  https://doi.org/10.1016/j.chembiol.2017.08.028CrossRefPubMedPubMedCentralGoogle Scholar
  54. Luo X, Nie J, Wang S, Chen Z, Chen W, Li D, Hu H, Li B (2015) Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J Biol Chem 290(48):28675–28682.  https://doi.org/10.1074/jbc.M115.661611CrossRefPubMedPubMedCentralGoogle Scholar
  55. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186(6):3299–3303.  https://doi.org/10.4049/jimmunol.1003613CrossRefPubMedPubMedCentralGoogle Scholar
  56. Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC (2014) Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40(5):692–705.  https://doi.org/10.1016/j.immuni.2014.04.007CrossRefPubMedPubMedCentralGoogle Scholar
  57. Ouyang W, Liao W, Luo CT, Yin N, Huse M, Kim MV, Peng M, Chan P, Ma Q, Mo Y, Meijer D, Zhao K, Rudensky AY, Atwal G, Zhang MQ, Li MO (2012) Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 491(7425):554–559.  https://doi.org/10.1038/nature11581CrossRefPubMedPubMedCentralGoogle Scholar
  58. Park Y, Jin H-S, Lopez J, Elly C, Kim G, Murai M, Kronenberg M, Liu Y-C (2013) TSC1 regulates the balance between effector and regulatory T cells. J Clin Investig 123(12):5165–5178.  https://doi.org/10.1172/jci69751CrossRefPubMedGoogle Scholar
  59. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460(7251):103–107.  https://doi.org/10.1038/nature08097CrossRefPubMedPubMedCentralGoogle Scholar
  60. Powell JD, Delgoffe GM (2010) The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33(3):301–311.  https://doi.org/10.1016/j.immuni.2010.09.002CrossRefPubMedPubMedCentralGoogle Scholar
  61. Procaccini C, De Rosa V, Galgani M, Abanni L, Cali G, Porcellini A, Carbone F, Fontana S, Horvath TL, La Cava A, Matarese G (2010) An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33(6):929–941.  https://doi.org/10.1016/j.immuni.2010.11.024CrossRefPubMedPubMedCentralGoogle Scholar
  62. Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M, Faicchia D, Marone G, Tramontano D, Corona M, Alviggi C, Porcellini A, La Cava A, Mauri P, Matarese G (2016) The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44(3):712.  https://doi.org/10.1016/j.immuni.2016.02.022CrossRefPubMedPubMedCentralGoogle Scholar
  63. Ramalingam R, Larmonier CB, Thurston RD, Midura-Kiela MT, Zheng SG, Ghishan FK, Kiela PR (2012) Dendritic cell-specific disruption of TGF-beta receptor II leads to altered regulatory T cell phenotype and spontaneous multiorgan autoimmunity. J Immunol 189(8):3878–3893.  https://doi.org/10.4049/jimmunol.1201029CrossRefPubMedPubMedCentralGoogle Scholar
  64. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D (2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365(22):2067–2077.  https://doi.org/10.1056/NEJMoa1105143CrossRefPubMedGoogle Scholar
  65. Samanta A, Li B, Song X, Bembas K, Zhang G, Katsumata M, Saouaf SJ, Wang Q, Hancock WW, Shen Y, Greene MI (2008) TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc Natl Acad Sci U S A 105(37):14023–14027.  https://doi.org/10.1073/pnas.0806726105CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM, Fisher AG, Merkenschlager M (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 105(22):7797–7802.  https://doi.org/10.1073/pnas.0800928105CrossRefPubMedPubMedCentralGoogle Scholar
  67. Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, Kondo J, Coffey RJ, Johnson MO, Rathmell JC, Sharick JT, Skala MC, Smith JA, Berlin J, Washington MK, Nickels ML, Manning HC (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24(2):194–202.  https://doi.org/10.1038/nm.4464CrossRefPubMedPubMedCentralGoogle Scholar
  68. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376.  https://doi.org/10.1084/jem.20110278CrossRefPubMedPubMedCentralGoogle Scholar
  69. Shi H, Chapman NM, Wen J, Guy C, Long L, Dhungana Y, Rankin S, Pelletier S, Vogel P, Wang H, Peng J, Guan KL, Chi H (2019) Amino acids license kinase mTORC1 activity and Treg cell function via small G proteins Rag and Rheb. Immunity 51(6):1012–1027 e1017.  https://doi.org/10.1016/j.immuni.2019.10.001CrossRefPubMedPubMedCentralGoogle Scholar
  70. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16(2):178–187.  https://doi.org/10.1038/ni.3076CrossRefPubMedPubMedCentralGoogle Scholar
  71. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14(5):500–508.  https://doi.org/10.1038/ni.2556CrossRefPubMedPubMedCentralGoogle Scholar
  72. Sinclair LV, Neyens D, Ramsay G, Taylor PM, Cantrell DA (2018) Single cell analysis of kynurenine and System L amino acid transport in T cells. Nat Commun 9(1):1981.  https://doi.org/10.1038/s41467-018-04366-7CrossRefPubMedPubMedCentralGoogle Scholar
  73. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341(6145):569–573.  https://doi.org/10.1126/science.1241165CrossRefGoogle Scholar
  74. Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ, Roberts LK, Wong CHY, Shim R, Robert R, Chevalier N, Tan JK, Mariño E, Moore RJ, Wong L, McConville MJ, Tull DL, Wood LG, Murphy VE, Mattes J, Gibson PG, Mackay CR (2015) Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun 6(1):7320.  https://doi.org/10.1038/ncomms8320CrossRefPubMedGoogle Scholar
  75. van Loosdregt J, Fleskens V, Fu J, Brenkman Arjan B, Bekker Cornelis PJ, Pals Cornelieke EGM, Meerding J, Berkers Celia R, Barbi J, Gröne A, Sijts Alice JAM, Maurice Madelon M, Kalkhoven E, Prakken Berent J, Ovaa H, Pan F, Zaiss Dietmar MW, Coffer Paul J (2013) Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39(2):259–271.  https://doi.org/10.1016/j.immuni.2013.05.018CrossRefPubMedPubMedCentralGoogle Scholar
  76. Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM, Martinez-Reyes I, Gao P, Helmin KA, Abdala-Valencia H, Sena LA, Schumacker PT, Turka LA, Chandel NS (2019) Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565(7740):495–499.  https://doi.org/10.1038/s41586-018-0846-zCrossRefPubMedPubMedCentralGoogle Scholar
  77. Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11(1):7–13.  https://doi.org/10.1038/ni.1818CrossRefPubMedGoogle Scholar
  78. Yan Y, Zhang G-X, Gran B, Fallarino F, Yu S, Li H, Cullimore ML, Rostami A, Xu H (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185(10):5953–5961.  https://doi.org/10.4049/jimmunol.1001628CrossRefPubMedPubMedCentralGoogle Scholar
  79. Yang S, Wang J, Brand DD, Zheng SG (2018) Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front Immunol 9:784.  https://doi.org/10.3389/fimmu.2018.00784CrossRefPubMedPubMedCentralGoogle Scholar
  80. Yang S, Xie C, Chen Y, Wang J, Chen X, Lu Z, June RR, Zheng SG (2019) Differential roles of TNFalpha-TNFR1 and TNFalpha-TNFR2 in the differentiation and function of CD4(+)Foxp3(+) induced Treg cells in vitro and in vivo periphery in autoimmune diseases. Cell Death Dis 10(1):27.  https://doi.org/10.1038/s41419-018-1266-6CrossRefPubMedPubMedCentralGoogle Scholar
  81. Ye C, Brand D, Zheng SG (2018) Targeting IL-2: an unexpected effect in treating immunological diseases. Signal Transduct Target Ther 3:2.  https://doi.org/10.1038/s41392-017-0002-5CrossRefPubMedPubMedCentralGoogle Scholar
  82. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490.  https://doi.org/10.1038/nature12297CrossRefPubMedPubMedCentralGoogle Scholar
  83. Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA (2002) Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J Immunol 169(8):4183–4189.  https://doi.org/10.4049/jimmunol.169.8.4183CrossRefPubMedGoogle Scholar
  84. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA (2007) IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 178(4):2018–2027CrossRefGoogle Scholar
  85. Zhou X, Kong N, Wang J, Fan H, Zou H, Horwitz D, Brand D, Liu Z, Zheng SG (2010) Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol 185(5):2675–2679.  https://doi.org/10.4049/jimmunol.1000598CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2021

Authors and Affiliations

  1. 1.Shanghai Institute of Immunology, Department of Immunology and MicrobiologyShanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
  2. 2.Bio-X Institutes, Shanghai Jiao Tong UniversityShanghaiChina
  3. 3.Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong UniversityShanghaiChina

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