Epigenetic regulation of T helper cells and intestinal pathogenicity

1.

Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133. https://doi.org/10.1016/j.cell.2006.07.035 CrossRefPubMed

2.

Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28:29–39. https://doi.org/10.1016/j.immuni.2007.11.016 CrossRefPubMed

3.

Zheng Y, Rudensky AY (2007) Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8:457–462. https://doi.org/10.1038/ni1455 CrossRefPubMed

4.

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.25.022106.141623 CrossRefPubMedPubMedCentral

5.

Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500. https://doi.org/10.1038/nri2785 CrossRefPubMed

6.

Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10:248–256. https://doi.org/10.1038/nri2742 CrossRefPubMedPubMedCentral

7.

Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489. https://doi.org/10.1146/annurev-immunol-030409-101212 CrossRefPubMedPubMedCentral

8.

O'Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y (2011) Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 11:239–250. https://doi.org/10.1038/nri2958 CrossRefPubMedPubMedCentral

9.

Bonelli M, Shih HY, Hirahara K, Singelton K, Laurence A, Poholek A, Hand T, Mikami Y, Vahedi G, Kanno Y, O'Shea JJ (2014) Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes. Curr Top Microbiol Immunol 381:279–326. https://doi.org/10.1007/82_2014_371 CrossRefPubMedPubMedCentral

10.

Allan RS, Zueva E, Cammas F, Schreiber HA, Masson V, Belz GT, Roche D, Maison C, Quivy JP, Almouzni G, Amigorena S (2012) An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 487:249–253. https://doi.org/10.1038/nature11173 CrossRefPubMed

11.

Rodriguez RM, Lopez-Larrea C, Suarez-Alvarez B (2015) Epigenetic dynamics during CD4(+) T cells lineage commitment. Int J Biochem Cell Biol 67:75–85. https://doi.org/10.1016/j.biocel.2015.04.020 CrossRefPubMed

12.

Kroesen BJ, Teteloshvili N, Smigielska-Czepiel K, Brouwer E, Boots AM, van den Berg A, Kluiver J (2015) Immuno-miRs: critical regulators of T-cell development, function and ageing. Immunology 144:1–10. https://doi.org/10.1111/imm.12367 CrossRefPubMed

13.

Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621. https://doi.org/10.1146/annurev-immunol-030409-101225 CrossRefPubMedPubMedCentral

14.

Littman DR, Rudensky AY (2010) Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140:845–858. https://doi.org/10.1016/j.cell.2010.02.021 CrossRefPubMed

15.

Honda K, Littman DR (2016) The microbiota in adaptive immune homeostasis and disease. Nature 535:75–84. https://doi.org/10.1038/nature18848 CrossRefPubMed

16.

Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, Duchmann R (2005) Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128:1868–1878CrossRefPubMed

17.

Saruta M, Yu QT, Fleshner PR, Mantel PY, Schmidt-Weber CB, Banham AH, Papadakis KA (2007) Characterization of FOXP3+CD4+ regulatory T cells in Crohn’s disease. Clin Immunol 125:281–290. https://doi.org/10.1016/j.clim.2007.08.003 CrossRefPubMed

18.

Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, Nakamura T, Koganei K, Fukushima T, Watanabe M (2004) CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 173:3119–3130CrossRefPubMed

19.

Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21. https://doi.org/10.1038/83713 CrossRefPubMed

20.

Kitagawa Y, Ohkura N, Sakaguchi S (2015) Epigenetic control of thymic Treg-cell development. Eur J Immunol 45:11–16. https://doi.org/10.1002/eji.201444577 CrossRefPubMed

21.

Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38:414–423. https://doi.org/10.1016/j.immuni.2013.03.002 CrossRefPubMed

22.

Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, Huehn J, Fehling HJ, Sparwasser T, Nakai K, Sakaguchi S (2012) T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37:785–799. https://doi.org/10.1016/j.immuni.2012.09.010 CrossRefPubMed

23.

Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–812. https://doi.org/10.1038/nature08750 CrossRefPubMedPubMedCentral

24.

Huehn J, Beyer M (2015) Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin Immunol 27:10–18. https://doi.org/10.1016/j.smim.2015.02.002 CrossRefPubMed

25.

Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky AY (2014) Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158:749–763. https://doi.org/10.1016/j.cell.2014.07.031 CrossRefPubMedPubMedCentral

26.

Li X, Liang Y, LeBlanc M, Benner C, Zheng Y (2014) Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158:734–748. https://doi.org/10.1016/j.cell.2014.07.030 CrossRefPubMedPubMedCentral

27.

Dominguez-Villar M, Hafler DA (2018) Regulatory T cells in autoimmune disease. Nat Immunol. https://doi.org/10.1038/s41590-018-0120-4

28.

Lu L, Barbi J, Pan F (2017) The regulation of immune tolerance by FOXP3. Nat Rev Immunol 17:703–717. https://doi.org/10.1038/nri.2017.75 CrossRefPubMedPubMedCentral

29.

Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38:1654–1663. https://doi.org/10.1002/eji.200838105 CrossRefPubMed

30.

Janson PC, Winerdal ME, Marits P, Thorn M, Ohlsson R, Winqvist O (2008) FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS One 3:e1612. https://doi.org/10.1371/journal.pone.0001612 CrossRefPubMedPubMedCentral

31.

Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, Lio CW, Li X, Huang Y, Vijayanand P, Lahdesmaki H, Rao A (2016) Control of Foxp3 stability through modulation of TET activity. J Exp Med 213:377–397. https://doi.org/10.1084/jem.20151438 CrossRefPubMedPubMedCentral

32.

Someya K, Nakatsukasa H, Ito M, Kondo T, Tateda KI, Akanuma T, Koya I, Sanosaka T, Kohyama J, Tsukada YI, Takamura-Enya T, Yoshimura A (2017) Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation. Int Immunol 29:365–375. https://doi.org/10.1093/intimm/dxx049 CrossRefPubMedPubMedCentral

33.

Reif S, Klein I, Lubin F, Farbstein M, Hallak A, Gilat T (1997) Pre-illness dietary factors in inflammatory bowel disease. Gut 40:754–760CrossRefPubMedPubMedCentral

34.

Wang L, Liu Y, Beier UH, Han R, Bhatti TR, Akimova T, Hancock WW (2013) Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood 121:3631–3639. https://doi.org/10.1182/blood-2012-08-451765 CrossRefPubMedPubMedCentral

35.

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 565:495–499. https://doi.org/10.1038/s41586-018-0846-z CrossRefPubMedPubMedCentral

36.

Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG (2006) Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177:8338–8347CrossRefPubMed

37.

Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B, Kuchroo VK (2008) Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 181:2277–2284CrossRefPubMed

38.

Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260. https://doi.org/10.1126/science.1145697 CrossRefPubMed

39.

Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D, Benoist C (2008) Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity 29:758–770. https://doi.org/10.1016/j.immuni.2008.09.018 CrossRefPubMedPubMedCentral

40.

Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A (2018) Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. Int Immunol 30:357–373. https://doi.org/10.1093/intimm/dxy043 CrossRefPubMed

41.

Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465. https://doi.org/10.1038/nri2093 CrossRefPubMed

42.

Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H (2018) Negative regulation of cytokine signaling in immunity. Cold Spring Harb Perspect Biol 10. https://doi.org/10.1101/cshperspect.a028571

43.

Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A, Morita R, Asakawa M, Chinen T, Yoshimura A (2011) SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 208:2055–2067. https://doi.org/10.1084/jem.20110428 CrossRefPubMedPubMedCentral

44.

Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–929. https://doi.org/10.1016/j.cell.2010.08.012 CrossRefPubMedPubMedCentral

45.

Takahashi R, Nakatsukasa H, Shiozawa S, Yoshimura A (2017) SOCS1 is a key molecule that prevents regulatory T cell plasticity under inflammatory conditions. J Immunol 199:149–158. https://doi.org/10.4049/jimmunol.1600441 CrossRefPubMed

46.

Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10:595–602. https://doi.org/10.1038/ni.1731 CrossRefPubMedPubMedCentral

47.

Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS, Harris TH, Grainger J, Wojno ED, Wagage S, Roos DS, Scott P, Turka LA, Cherry S, Reiner SL, Cua D, Belkaid Y, Elloso MM, Hunter CA (2012) The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37:511–523. https://doi.org/10.1016/j.immuni.2012.06.014 CrossRefPubMedPubMedCentral

48.

Levine AG, Mendoza A, Hemmers S, Moltedo B, Niec RE, Schizas M, Hoyos BE, Putintseva EV, Chaudhry A, Dikiy S, Fujisawa S, Chudakov DM, Treuting PM, Rudensky AY (2017) Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546:421–425. https://doi.org/10.1038/nature22360 CrossRefPubMedPubMedCentral

49.

Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R, Paul WE, Bosselut R, Wei G, Zhao K, Oukka M, Zhu J, Belkaid Y (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 121:4503–4515. https://doi.org/10.1172/jci57456 CrossRefPubMedPubMedCentral

50.

Delacher M, Imbusch CD, Weichenhan D, Breiling A, Hotz-Wagenblatt A, Trager U, Hofer AC, Kagebein D, Wang Q, Frauhammer F, Mallm JP, Bauer K, Herrmann C, Lang PA, Brors B, Plass C, Feuerer M (2017) Corrigendum: genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat Immunol 18:1361. https://doi.org/10.1038/ni1217-1361b CrossRefPubMed

51.

Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BMJ, Lohning M, Belkaid Y, Fallon PG, Powrie F (2014) The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513:564–568. https://doi.org/10.1038/nature13577 CrossRefPubMedPubMedCentral

52.

Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486:549–553. https://doi.org/10.1038/nature11132 CrossRefPubMedPubMedCentral

53.

Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C, Mathis D (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155:1282–1295. https://doi.org/10.1016/j.cell.2013.10.054 CrossRefPubMedPubMedCentral

54.

Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, Treuting PM, Rudensky AY (2015) A distinct function of regulatory T cells in tissue protection. Cell 162:1078–1089. https://doi.org/10.1016/j.cell.2015.08.021 CrossRefPubMedPubMedCentral

55.

Panduro M, Benoist C, Mathis D (2016) Tissue Tregs. Annu Rev Immunol 34:609–633. https://doi.org/10.1146/annurev-immunol-032712-095948 CrossRefPubMedPubMedCentral

56.

Ito M, Komai K, Mise-Omata S, Iizuka-Koga M, Noguchi Y, Kondo T, Sakai R, Matsuo K, Nakayama T, Yoshie O, Nakatsukasa H, Chikuma S, Shichita T, Yoshimura A (2019) Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature. https://doi.org/10.1038/s41586-018-0824-5

57.

Matta BM, Reichenbach DK, Zhang X, Mathews L, Koehn BH, Dwyer GK, Lott JM, Uhl FM, Pfeifer D, Feser CJ, Smith MJ, Liu Q, Zeiser R, Blazar BR, Turnquist HR (2016) Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood 128:427–439. https://doi.org/10.1182/blood-2015-12-684142 CrossRefPubMedPubMedCentral

58.

Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, Scarpa M, Fiocchi C, Vecchi M, Pizarro TT (2010) Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S A 107:8017–8022. https://doi.org/10.1073/pnas.0912678107 CrossRefPubMedPubMedCentral

59.

Verheijden KA, Akbari P, Willemsen LE, Kraneveld AD, Folkerts G, Garssen J, Fink-Gremmels J, Braber S (2015) Inflammation-induced expression of the alarmin interleukin 33 can be suppressed by galacto-oligosaccharides. Int Arch Allergy Immunol 167:127–136. https://doi.org/10.1159/000437327 CrossRefPubMed

60.

Peine M, Marek RM, Lohning M (2016) IL-33 in T cell differentiation, function, and immune homeostasis. Trends Immunol 37:321–333. https://doi.org/10.1016/j.it.2016.03.007 CrossRefPubMed

61.

Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490. https://doi.org/10.1016/j.immuni.2005.09.015 CrossRefPubMed

62.

Monteleone G, Trapasso F, Parrello T, Biancone L, Stella A, Iuliano R, Luzza F, Fusco A, Pallone F (1999) Bioactive IL-18 expression is up-regulated in Crohn’s disease. J Immunol 163:143–147PubMed

63.

Pizarro TT, Michie MH, Bentz M, Woraratanadharm J, Smith MF Jr, Foley E, Moskaluk CA, Bickston SJ, Cominelli F (1999) IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol 162:6829–6835PubMed

64.

Kanai T, Watanabe M, Okazawa A, Sato T, Yamazaki M, Okamoto S, Ishii H, Totsuka T, Iiyama R, Okamoto R, Ikeda M, Kurimoto M, Takeda K, Akira S, Hibi T (2001) Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. Gastroenterology 121:875–888CrossRefPubMed

65.

Ten Hove T, Corbaz A, Amitai H, Aloni S, Belzer I, Graber P, Drillenburg P, van Deventer SJ, Chvatchko Y, Te Velde AA (2001) Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology 121:1372–1379CrossRefPubMed

66.

Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW, Bailis W, Low JS, Harman CC, Graham M, Elinav E, Flavell RA (2015) Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163:1444–1456. https://doi.org/10.1016/j.cell.2015.10.072 CrossRefPubMedPubMedCentral

67.

Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, Meunier C, Turbide C, Gros P, Beauchemin N, Vallance BA, Saleh M (2010) Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32:367–378. https://doi.org/10.1016/j.immuni.2010.02.012 CrossRefPubMed

68.

Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391. https://doi.org/10.1016/j.immuni.2010.03.003 CrossRefPubMedPubMedCentral

69.

Harrison OJ, Srinivasan N, Pott J, Schiering C, Krausgruber T, Ilott NE, Maloy KJ (2015) Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3(+) Treg cell function in the intestine. Mucosal Immunol 8:1226–1236. https://doi.org/10.1038/mi.2015.13 CrossRefPubMedPubMedCentral

70.

Xiao Y, Nagai Y, Deng G, Ohtani T, Zhu Z, Zhou Z, Zhang H, Ji MQ, Lough JW, Samanta A, Hancock WW, Greene MI (2014) Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep 7:1471–1480. https://doi.org/10.1016/j.celrep.2014.04.021 CrossRefPubMedPubMedCentral

71.

Chen Z, Barbi J, Bu S, Yang HY, 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 BV, Pan Z, Zhang J, Dang E, Li Z, Wang H, Luo W, Li L, Semenza GL, Zheng SG, Loser K, Tsun A, Greene MI, Pardoll DM, 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 39:272–285. https://doi.org/10.1016/j.immuni.2013.08.006 CrossRefPubMed

72.

van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YY, Beekman JM, van Beekum O, Brenkman AB, Hijnen DJ, Mutis T, Kalkhoven E, Prakken BJ, Coffer PJ (2010) Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115:965–974. https://doi.org/10.1182/blood-2009-02-207118 CrossRefPubMed

73.

Chen Y, Chen C, Zhang Z, Liu CC, Johnson ME, Espinoza CA, Edsall LE, Ren B, Zhou XJ, Grant SF, Wells AD, Chen L (2015) DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions. Nucleic Acids Res 43:1268–1282. https://doi.org/10.1093/nar/gku1373 CrossRefPubMedPubMedCentral

74.

Ruan Q, Kameswaran V, Tone Y, Li L, Liou HC, Greene MI, Tone M, Chen YH (2009) Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31:932–940. https://doi.org/10.1016/j.immuni.2009.10.006 CrossRefPubMedPubMedCentral

75.

Baine I, Basu S, Ames R, Sellers RS, Macian F (2013) Helios induces epigenetic silencing of IL2 gene expression in regulatory T cells. J Immunol 190:1008–1016. https://doi.org/10.4049/jimmunol.1200792 CrossRefPubMed

76.

Malek TR, Yu A, Vincek V, Scibelli P, Kong L (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178CrossRefPubMed

77.

Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C (1998) Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol 10:371–378CrossRefPubMed

78.

Almeida AR, Legrand N, Papiernik M, Freitas AA (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169:4850–4860CrossRefPubMed

79.

Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178:280–290CrossRefPubMed

80.

Van Assche G, Sandborn WJ, Feagan BG, Salzberg BA, Silvers D, Monroe PS, Pandak WM, Anderson FH, Valentine JF, Wild GE, Geenen DJ, Sprague R, Targan SR, Rutgeerts P, Vexler V, Young D, Shames RS (2006) Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut 55:1568–1574. https://doi.org/10.1136/gut.2005.089854 CrossRefPubMedPubMedCentral

81.

Sands BE, Sandborn WJ, Creed TJ, Dayan CM, Dhanda AD, Van Assche GA, Gregus M, Sood A, Choudhuri G, Stempien MJ, Levitt D, Probert CS (2012) Basiliximab does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis. Gastroenterology 143:356-364.e351. https://doi.org/10.1053/j.gastro.2012.04.043 CrossRef

82.

Huss DJ, Mehta DS, Sharma A, You X, Riester KA, Sheridan JP, Amaravadi LS, Elkins JS, Fontenot JD (2015) In vivo maintenance of human regulatory T cells during CD25 blockade. J Immunol 194:84–92. https://doi.org/10.4049/jimmunol.1402140 CrossRefPubMed

83.

Villarino A, Laurence A, Robinson GW, Bonelli M, Dema B, Afzali B, Shih HY, Sun HW, Brooks SR, Hennighausen L, Kanno Y, O'Shea JJ (2016) Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. Elife 5. https://doi.org/10.7554/eLife.08384

84.

Sari NK, Setiati S, Taher A, Wiwie M, Djauzi S, Pandelaki J, Purba JS, Sadikin M (2017) The role of autosuggestion in geriatric patients’ quality of life: a study on psycho-neuro-endocrine-immunology pathway. Soc Neurosci 12:551–559. https://doi.org/10.1080/17470919.2016.1196243 CrossRefPubMed

85.

Liao W, Schones DE, Oh J, Cui Y, Cui K, Roh TY, Zhao K, Leonard WJ (2008) Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol 9:1288–1296. https://doi.org/10.1038/ni.1656 CrossRefPubMedPubMedCentral

86.

Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M, Sciume G, Zare H, Vahedi G, Dema B, Yu Z, Liu H, Takahashi H, Rao M, Muranski P, Crompton JG, Punkosdy G, Bedognetti D, Wang E, Hoffmann V, Rivera J, Marincola FM, Nakamura A, Sartorelli V, Kanno Y, Gattinoni L, Muto A, Igarashi K, O'Shea JJ, Restifo NP (2013) BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 498:506–510. https://doi.org/10.1038/nature12199 CrossRefPubMedPubMedCentral

87.

Afzali B, Gronholm J, Vandrovcova J, O'Brien C, Sun HW, Vanderleyden I, Davis FP, Khoder A, Zhang Y, Hegazy AN, Villarino AV, Palmer IW, Kaufman J, Watts NR, Kazemian M, Kamenyeva O, Keith J, Sayed A, Kasperaviciute D, Mueller M, Hughes JD, Fuss IJ, Sadiyah MF, Montgomery-Recht K, McElwee J, Restifo NP, Strober W, Linterman MA, Wingfield PT, Uhlig HH, Roychoudhuri R, Aitman TJ, Kelleher P, Lenardo MJ, O'Shea JJ, Cooper N, Laurence ADJ (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18:813–823. https://doi.org/10.1038/ni.3753 CrossRefPubMedPubMedCentral

88.

Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY (2016) An essential role for the IL-2 receptor in Treg cell function. Nat Immunol 17:1322–1333. https://doi.org/10.1038/ni.3540 CrossRefPubMedPubMedCentral

89.

Schwartz DM, O’Shea JJ (2019) Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program to reduce allergic pathology. Immunity 50(1):106–120.e10. https://doi.org/10.1016/j.immuni.2018.12.014

90.

Bai A, Lu N, Zeng H, Li Z, Zhou X, Chen J, Liu P, Peng Z, Guo Y (2010) All-trans retinoic acid ameliorates trinitrobenzene sulfonic acid-induced colitis by shifting Th1 to Th2 profile. J Interf Cytokine Res 30:399–406. https://doi.org/10.1089/jir.2009.0028 CrossRef

91.

Hong K, Zhang Y, Guo Y, Xie J, Wang J, He X, Lu N, Bai A (2014) All-trans retinoic acid attenuates experimental colitis through inhibition of NF-kappaB signaling. Immunol Lett 162:34–40. https://doi.org/10.1016/j.imlet.2014.06.011 CrossRefPubMed

92.

Povoleri GAM, Nova-Lamperti E, Scotta C, Fanelli G, Chen YC, Becker PD, Boardman D, Costantini B, Romano M, Pavlidis P, McGregor R, Pantazi E, Chauss D, Sun HW, Shih HY, Cousins DJ, Cooper N, Powell N, Kemper C, Pirooznia M, Laurence A, Kordasti S, Kazemian M, Lombardi G, Afzali B (2018) Human retinoic acid-regulated CD161(+) regulatory T cells support wound repair in intestinal mucosa. Nat Immunol 19:1403–1414. https://doi.org/10.1038/s41590-018-0230-z CrossRefPubMedPubMedCentral

93.

Prevost N, English JC (2013) Isotretinoin: update on controversial issues. J Pediatr Adolesc Gynecol 26:290–293CrossRefPubMed

94.

Reddy D, Siegel CA, Sands BE, Kane S (2006) Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 101:1569–1573. https://doi.org/10.1111/j.1572-0241.2006.00632.x CrossRefPubMed

95.

Hippen KL, Loschi M, Nicholls J, MacDonald KPA, Blazar BR (2018) Effects of MicroRNA on regulatory T cells and implications for adoptive cellular therapy to ameliorate graft-versus-host disease. Front Immunol 9:57. https://doi.org/10.3389/fimmu.2018.00057 CrossRefPubMedPubMedCentral

96.

Baumjohann D, Ansel KM (2013) MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 13:666–678. https://doi.org/10.1038/nri3494 CrossRefPubMedPubMedCentral

97.

Fayyad-Kazan H, Rouas R, Fayyad-Kazan M, Badran R, El Zein N, Lewalle P, Najar M, Hamade E, Jebbawi F, Merimi M, Romero P, Burny A, Badran B, Martiat P (2012) MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of differentially expressed microRNAs on expression of two genes essential to their function. J Biol Chem 287:9910–9922. https://doi.org/10.1074/jbc.M111.337154 CrossRefPubMedPubMedCentral

98.

Liu SQ, Jiang S, Li C, Zhang B, Li QJ (2014) miR-17-92 cluster targets phosphatase and tensin homology and Ikaros family zinc finger 4 to promote TH17-mediated inflammation. J Biol Chem 289:12446–12456. https://doi.org/10.1074/jbc.M114.550723 CrossRefPubMedPubMedCentral

99.

Dong L, Wang X, Tan J, Li H, Qian W, Chen J, Chen Q, Wang J, Xu W, Tao C, Wang S (2014) Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis. J Cell Mol Med 18:2213–2224. https://doi.org/10.1111/jcmm.12353 CrossRefPubMedPubMedCentral

100.

Dooley J, Linterman MA, Liston A (2013) MicroRNA regulation of T-cell development. Immunol Rev 253:53–64. https://doi.org/10.1111/imr.12049 CrossRefPubMed

101.

Lu LF, Gasteiger G, Yu IS, Chaudhry A, Hsin JP, Lu Y, Bos PD, Lin LL, Zawislak CL, Cho S, Sun JC, Leslie CS, Lin SW, Rudensky AY (2015) A single miRNA-mRNA interaction affects the immune response in a context- and cell-type-specific manner. Immunity 43:52–64. https://doi.org/10.1016/j.immuni.2015.04.022 CrossRefPubMedPubMedCentral

102.

Beyer M, Thabet Y, Muller RU, Sadlon T, Classen S, Lahl K, Basu S, Zhou X, Bailey-Bucktrout SL, Krebs W, Schonfeld EA, Bottcher J, Golovina T, Mayer CT, Hofmann A, Sommer D, Debey-Pascher S, Endl E, Limmer A, Hippen KL, Blazar BR, Balderas R, Quast T, Waha A, Mayer G, Famulok M, Knolle PA, Wickenhauser C, Kolanus W, Schermer B, Bluestone JA, Barry SC, Sparwasser T, Riley JL, Schultze JL (2011) Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol 12:898–907. https://doi.org/10.1038/ni.2084 CrossRefPubMedPubMedCentral

103.

Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, Yasuda K, Motooka D, Nakamura S, Kondo M, Taniuchi I, Kohwi-Shigematsu T, Sakaguchi S (2017) Addendum: guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol 18:1270. https://doi.org/10.1038/ni1117-1270a CrossRefPubMed

104.

Yang HY, Barbi J, Wu CY, Zheng Y, Vignali PD, Wu X, Tao JH, Park BV, Bandara S, Novack L, Ni X, Yang X, Chang KY, Wu RC, Zhang J, Yang CW, Pardoll DM, Li H, Pan F (2016) MicroRNA-17 modulates regulatory T cell function by targeting co-regulators of the Foxp3 transcription factor. Immunity 45:83–93. https://doi.org/10.1016/j.immuni.2016.06.022 CrossRefPubMedPubMedCentral

105.

Cruz LO, Hashemifar SS, Wu CJ, Cho S, Nguyen DT, Lin LL, Khan AA, Lu LF (2017) Excessive expression of miR-27 impairs Treg-mediated immunological tolerance. J Clin Invest 127:530–542. https://doi.org/10.1172/jci88415 CrossRefPubMedPubMedCentral

106.

Zemmour D, Pratama A, Loughhead SM, Mathis D, Benoist C (2017) Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity. Proc Natl Acad Sci U S A 114:E3472–e3480. https://doi.org/10.1073/pnas.1700946114 CrossRefPubMedPubMedCentral

107.

Brajic A, Franckaert D, Burton O, Bornschein S, Calvanese AL, Demeyer S, Cools J, Dooley J, Schlenner S, Liston A (2018) The long non-coding RNA Flatr anticipates Foxp3 expression in regulatory T cells. Front Immunol 9:1989. https://doi.org/10.3389/fimmu.2018.01989 CrossRefPubMedPubMedCentral

108.

Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH (2002) Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295:338–342. https://doi.org/10.1126/science.1065543 CrossRefPubMed

109.

Peng SL (2006) The T-box transcription factor T-bet in immunity and autoimmunity. Cell Mol Immunol 3:87–95PubMed

110.

Lugo-Villarino G, Maldonado-Lopez R, Possemato R, Penaranda C, Glimcher LH (2003) T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells. Proc Natl Acad Sci U S A 100:7749–7754. https://doi.org/10.1073/pnas.1332767100 CrossRefPubMedPubMedCentral

111.

Iqbal N, Oliver JR, Wagner FH, Lazenby AS, Elson CO, Weaver CT (2002) T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis. J Exp Med 195:71–84CrossRefPubMedPubMedCentral

112.

Ito R, Shin-Ya M, Kishida T, Urano A, Takada R, Sakagami J, Imanishi J, Kita M, Ueda Y, Iwakura Y, Kataoka K, Okanoue T, Mazda O (2006) Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice. Clin Exp Immunol 146:330–338. https://doi.org/10.1111/j.1365-2249.2006.03214.x CrossRefPubMedPubMedCentral

113.

Muzes G, Molnar B, Tulassay Z, Sipos F (2012) Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol 18:5848–5861. https://doi.org/10.3748/wjg.v18.i41.5848 CrossRefPubMedPubMedCentral

114.

Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN, Glimcher LH (2007) Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131:33–45. https://doi.org/10.1016/j.cell.2007.08.017 CrossRefPubMedPubMedCentral

115.

Zimmermann J, Durek P, Kuhl AA, Schattenberg F, Maschmeyer P, Siracusa F, Lehmann K, Westendorf K, Weber M, Riedel R, Muller S, Radbruch A, Chang HD (2018) The intestinal microbiota determines the colitis-inducing potential of T-bet-deficient Th cells in mice. Eur J Immunol 48:161–167. https://doi.org/10.1002/eji.201747100 CrossRefPubMed

116.

Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3:521–533. https://doi.org/10.1038/nri1132 CrossRefPubMed

117.

Hommes DW, Mikhajlova TL, Stoinov S, Stimac D, Vucelic B, Lonovics J, Zakuciova M, D'Haens G, Van Assche G, Ba S, Lee S, Pearce T (2006) Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut 55:1131–1137. https://doi.org/10.1136/gut.2005.079392 CrossRefPubMedPubMedCentral

118.

Reinisch W, de Villiers W, Bene L, Simon L, Racz I, Katz S, Altorjay I, Feagan B, Riff D, Bernstein CN, Hommes D, Rutgeerts P, Cortot A, Gaspari M, Cheng M, Pearce T, Sands BE (2010) Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 16:233–242. https://doi.org/10.1002/ibd.21038 CrossRefPubMed

119.

Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, Ghosh S, de Villiers WJ, Panaccione R, Greenberg G, Schreiber S, Lichtiger S, Feagan BG (2012) Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 367:1519–1528. https://doi.org/10.1056/NEJMoa1203572 CrossRefPubMed

120.

Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669CrossRefPubMed

121.

Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE (2005) T-box genes in vertebrate development. Annu Rev Genet 39:219–239. https://doi.org/10.1146/annurev.genet.39.073003.105925 CrossRefPubMed

122.

Iwata S, Mikami Y, Sun HW, Brooks SR, Jankovic D, Hirahara K, Onodera A, Shih HY, Kawabe T, Jiang K, Nakayama T, Sher A, O'Shea JJ, Davis FP, Kanno Y (2017) The transcription factor T-bet limits amplification of type I IFN transcriptome and circuitry in T helper 1 cells. Immunity 46:983-991.e984. https://doi.org/10.1016/j.immuni.2017.05.005 CrossRef

123.

Kanno Y, Vahedi G, Hirahara K, Singleton K, O'Shea JJ (2012) Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 30:707–731. https://doi.org/10.1146/annurev-immunol-020711-075058 CrossRefPubMedPubMedCentral

124.

Wilson CB, Makar KW, Perez-Melgosa M (2002) Epigenetic regulation of T cell fate and function. J Infect Dis 185(Suppl 1):S37–S45. https://doi.org/10.1086/338001 CrossRefPubMed

125.

Thomas RM, Gamper CJ, Ladle BH, Powell JD, Wells AD (2012) De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem 287:22900–22909. https://doi.org/10.1074/jbc.M111.312785 CrossRefPubMedPubMedCentral

126.

Gonsky R, Deem RL, Landers CJ, Derkowski CA, Berel D, McGovern DP, Targan SR (2011) Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens. Inflamm Bowel Dis 17:171–178. https://doi.org/10.1002/ibd.21352 CrossRefPubMed

127.

Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V, Kanno Y, O'Shea JJ (2012) STATs shape the active enhancer landscape of T cell populations. Cell 151:981–993. https://doi.org/10.1016/j.cell.2012.09.044 CrossRefPubMedPubMedCentral

128.

Koues OI, Collins PL, Cella M, Robinette ML, Porter SI, Pyfrom SC, Payton JE, Colonna M, Oltz EM (2016) Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells. Cell 165:1134–1146. https://doi.org/10.1016/j.cell.2016.04.014 CrossRefPubMedPubMedCentral

129.

Gury-BenAri M, Thaiss CA, Serafini N, Winter DR, Giladi A, Lara-Astiaso D, Levy M, Salame TM, Weiner A, David E, Shapiro H, Dori-Bachash M, Pevsner-Fischer M, Lorenzo-Vivas E, Keren-Shaul H, Paul F, Harmelin A, Eberl G, Itzkovitz S, Tanay A, Di Santo JP, Elinav E, Amit I (2016) The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 166:1231-1246.e1213. https://doi.org/10.1016/j.cell.2016.07.043 CrossRef

130.

Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298:1039–1043. https://doi.org/10.1126/science.1076997 CrossRefPubMed

131.

Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Zeste protein. Genes Dev 16:2893–2905. https://doi.org/10.1101/gad.1035902 CrossRefPubMedPubMedCentral

132.

Schwartz YB, Pirrotta V (2013) A new world of Polycombs: unexpected partnerships and emerging functions. Nat Rev Genet 14:853–864. https://doi.org/10.1038/nrg3603 CrossRefPubMed

133.

Zhang Y, Kinkel S, Maksimovic J, Bandala-Sanchez E, Tanzer MC, Naselli G, Zhang JG, Zhan Y, Lew AM, Silke J, Oshlack A, Blewitt ME, Harrison LC (2014) The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 124:737–749. https://doi.org/10.1182/blood-2013-12-544106 CrossRefPubMed

134.

Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, Hosokawa H, Koseki H, Tokoyoda K, Suzuki Y, Motohashi S, Nakayama T (2013) The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity 39:819–832. https://doi.org/10.1016/j.immuni.2013.09.012 CrossRefPubMed

135.

Liu Y, Peng J, Sun T, Li N, Zhang L, Ren J, Yuan H, Kan S, Pan Q, Li X, Ding Y, Jiang M, Cong X, Tan M, Ma Y, Fu D, Cai S, Xiao Y, Wang X, Qin J (2017) Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFalpha-mediated inflammation and apoptosis. Proc Natl Acad Sci U S A 114:E3796–e3805. https://doi.org/10.1073/pnas.1700909114 CrossRefPubMedPubMedCentral

136.

McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, Tian X, Kruger RG, McHugh CF, Brandt M, Miller WH, Dhanak D, Verma SK, Tummino PJ, Creasy CL (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–112. https://doi.org/10.1038/nature11606 CrossRefPubMed

137.

Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E, Zhao L, Wei S, Frankel T, Vatan L, Szeliga W, Dou Y, Owens S, Marquez V, Tao K, Huang E, Wang G, Zou W (2016) PRC2 epigenetically silences Th1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res 76:275–282. https://doi.org/10.1158/0008-5472.Can-15-1938 CrossRefPubMed

138.

Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K (2007) UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449:731–734. https://doi.org/10.1038/nature06145 CrossRefPubMed

139.

Swigut T, Wysocka J (2007) H3K27 demethylases, at long last. Cell 131:29–32. https://doi.org/10.1016/j.cell.2007.09.026 CrossRefPubMed

140.

Miller SA, Mohn SE, Weinmann AS (2010) Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell 40:594–605. https://doi.org/10.1016/j.molcel.2010.10.028 CrossRefPubMedPubMedCentral

141.

Zhao W, Li Q, Ayers S, Gu Y, Shi Z, Zhu Q, Chen Y, Wang HY, Wang RF (2013) Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. Cell 152:1037–1050. https://doi.org/10.1016/j.cell.2013.02.006 CrossRefPubMedPubMedCentral

142.

Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K, Wang HY, Wang RF (2014) Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun 5:5780. https://doi.org/10.1038/ncomms6780 CrossRefPubMed

143.

Liu Z, Cao W, Xu L, Chen X, Zhan Y, Yang Q, Liu S, Chen P, Jiang Y, Sun X, Tao Y, Hu Y, Li C, Wang Q, Wang Y, Chen CD, Shi Y, Zhang X (2015) The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. J Mol Cell Biol 7:505–516. https://doi.org/10.1093/jmcb/mjv022 CrossRefPubMed

144.

Hangauer MJ, Vaughn IW, McManus MT (2013) Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet 9:e1003569. https://doi.org/10.1371/journal.pgen.1003569 CrossRefPubMedPubMedCentral

145.

Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166. https://doi.org/10.1146/annurev-biochem-051410-092902 CrossRefPubMed

146.

Chen YG, Satpathy AT, Chang HY (2017) Gene regulation in the immune system by long noncoding RNAs. Nat Immunol 18:962–972. https://doi.org/10.1038/ni.3771 CrossRefPubMed

147.

Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefPubMed

148.

Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–862CrossRefPubMed

149.

Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH (2008) MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology 135:1624-1635.e1624. https://doi.org/10.1053/j.gastro.2008.07.068 CrossRef

150.

Vigneau S, Rohrlich PS, Brahic M, Bureau JF (2003) Tmevpg1, a candidate gene for the control of Theiler’s virus persistence, could be implicated in the regulation of gamma interferon. J Virol 77:5632–5638CrossRefPubMedPubMedCentral

151.

Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM (2012) Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol 189:2084–2088. https://doi.org/10.4049/jimmunol.1200774 CrossRefPubMed

152.

Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard K (2013) The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152:743–754. https://doi.org/10.1016/j.cell.2013.01.015 CrossRefPubMedPubMedCentral

153.

Padua D, Mahurkar-Joshi S, Law IK, Polytarchou C, Vu JP, Pisegna JR, Shih D, Iliopoulos D, Pothoulakis C (2016) A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation. Am J Physiol Gastrointest Liver Physiol 311:G446–G457. https://doi.org/10.1152/ajpgi.00212.2016 CrossRefPubMedPubMedCentral

154.

Malik R, Patel L, Prensner JR, Shi Y, Iyer MK, Subramaniyan S, Carley A, Niknafs YS, Sahu A, Han S, Ma T, Liu M, Asangani IA, Jing X, Cao X, Dhanasekaran SM, Robinson DR, Feng FY, Chinnaiyan AM (2014) The lncRNA PCAT29 inhibits oncogenic phenotypes in prostate cancer. Mol Cancer Res 12:1081–1087. https://doi.org/10.1158/1541-7786.Mcr-14-0257 CrossRefPubMedPubMedCentral

155.

Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155 inhibits IFN-gamma signaling in CD4+ T cells. Eur J Immunol 40:225–231. https://doi.org/10.1002/eji.200939381 CrossRefPubMedPubMedCentral

156.

Beres NJ, Szabo D, Kocsis D, Szucs D, Kiss Z, Muller KE, Lendvai G, Kiss A, Arato A, Sziksz E, Vannay A, Szabo AJ, Veres G (2016) Role of altered expression of miR-146a, miR-155, and miR-122 in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 22:327–335. https://doi.org/10.1097/mib.0000000000000687 CrossRefPubMed

157.

Svrcek M, El-Murr N, Wanherdrick K, Dumont S, Beaugerie L, Cosnes J, Colombel JF, Tiret E, Flejou JF, Lesuffleur T, Duval A (2013) Overexpression of microRNAs-155 and 21 targeting mismatch repair proteins in inflammatory bowel diseases. Carcinogenesis 34:828–834. https://doi.org/10.1093/carcin/bgs408 CrossRefPubMed

158.

Jiang S, Li C, Olive V, Lykken E, Feng F, Sevilla J, Wan Y, He L, Li QJ (2011) Molecular dissection of the miR-17-92 cluster’s critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood 118:5487–5497. https://doi.org/10.1182/blood-2011-05-355644 CrossRefPubMedPubMedCentral

159.

Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R, Ansel KM (2011) MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. Immunity 35:169–181. https://doi.org/10.1016/j.immuni.2011.07.009 CrossRefPubMedPubMedCentral

160.

Mohnle P, Schutz SV, van der Heide V, Hubner M, Luchting B, Sedlbauer J, Limbeck E, Hinske LC, Briegel J, Kreth S (2015) MicroRNA-146a controls Th1-cell differentiation of human CD4+ T lymphocytes by targeting PRKCepsilon. Eur J Immunol 45:260–272. https://doi.org/10.1002/eji.201444667 CrossRefPubMed

161.

Zhou M, Ouyang W (2003) The function role of GATA-3 in Th1 and Th2 differentiation. Immunol Res 28:25–37. https://doi.org/10.1385/ir:28:1:25 CrossRefPubMed

162.

Kanhere A, Hertweck A, Bhatia U, Gokmen MR, Perucha E, Jackson I, Lord GM, Jenner RG (2012) T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Commun 3:1268. https://doi.org/10.1038/ncomms2260 CrossRefPubMed

163.

Mannon P, Reinisch W (2012) Interleukin 13 and its role in gut defence and inflammation. Gut 61:1765–1773. https://doi.org/10.1136/gutjnl-2012-303461 CrossRefPubMed

164.

Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497. https://doi.org/10.1172/jci19836 CrossRefPubMedPubMedCentral

165.

McKenzie GJ, Emson CL, Bell SE, Anderson S, Fallon P, Zurawski G, Murray R, Grencis R, McKenzie AN (1998) Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9:423–432CrossRefPubMed

166.

Inoue S, Matsumoto T, Iida M, Mizuno M, Kuroki F, Hoshika K, Shimizu M (1999) Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity. Am J Gastroenterol 94:2441–2446. https://doi.org/10.1111/j.1572-0241.1999.01372.x CrossRefPubMed

167.

Reinisch W, Panes J, Khurana S, Toth G, Hua F, Comer GM, Hinz M, Page K, O'Toole M, Moorehead TM, Zhu H, Sun Y, Cataldi F (2015) Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study. Gut 64:894–900. https://doi.org/10.1136/gutjnl-2014-308337 CrossRefPubMed

168.

Danese S, Rudzinski J, Brandt W, Dupas JL, Peyrin-Biroulet L, Bouhnik Y, Kleczkowski D, Uebel P, Lukas M, Knutsson M, Erlandsson F, Hansen MB, Keshav S (2015) Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 64:243–249. https://doi.org/10.1136/gutjnl-2014-308004 CrossRefPubMed

169.

Kole A, Maloy KJ (2014) Control of intestinal inflammation by interleukin-10. Curr Top Microbiol Immunol 380:19–38. https://doi.org/10.1007/978-3-662-43492-5_2 CrossRefPubMed

170.

Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–274CrossRefPubMed

171.

Tomoyose M, Mitsuyama K, Ishida H, Toyonaga A, Tanikawa K (1998) Role of interleukin-10 in a murine model of dextran sulfate sodium-induced colitis. Scand J Gastroenterol 33:435–440CrossRefPubMed

172.

Duchmann R, Schmitt E, Knolle P, Meyer zum Buschenfelde KH, Neurath M (1996) Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol 26:934–938. https://doi.org/10.1002/eji.1830260432 CrossRefPubMed

173.

Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361:2033–2045. https://doi.org/10.1056/NEJMoa0907206 CrossRefPubMedPubMedCentral

174.

van Deventer SJ, Elson CO, Fedorak RN (1997) Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn’s Disease Study Group Gastroenterology 113:383–389

175.

Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, Hanauer SB, Kilian A, Cohard M, LeBeaut A, Feagan B (2000) Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn’s disease. The interleukin 10 inflammatory bowel disease cooperative study group. Gastroenterology 119:1473–1482CrossRefPubMed

176.

Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S, Jacyna M, Lashner BA, Gangl A, Rutgeerts P, Isaacs K, van Deventer SJ, Koningsberger JC, Cohard M, LeBeaut A, Hanauer SB (2000) Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn’s disease IL-10 cooperative study group. Gastroenterology 119:1461–1472CrossRefPubMed

177.

Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625. https://doi.org/10.1038/nature07008 CrossRefPubMed

178.

Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottiere HM, Dore J, Marteau P, Seksik P, Langella P (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105:16731–16736. https://doi.org/10.1073/pnas.0804812105 CrossRefPubMedPubMedCentral

179.

Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–341. https://doi.org/10.1126/science.1198469 CrossRefPubMed

180.

Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–236. https://doi.org/10.1038/nature12331 CrossRefPubMed

181.

Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T, Hibi T, Roers A, Yagita H, Ohteki T, Yoshimura A, Kanai T (2013) A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice. Cell Host Microbe 13:711–722. https://doi.org/10.1016/j.chom.2013.05.013 CrossRefPubMed

182.

Kashiwagi I, Morita R, Schichita T, Komai K, Saeki K, Matsumoto M, Takeda K, Nomura M, Hayashi A, Kanai T, Yoshimura A (2015) Smad2 and Smad3 inversely regulate TGF-beta autoinduction in Clostridium butyricum-activated dendritic cells. Immunity 43:65–79. https://doi.org/10.1016/j.immuni.2015.06.010 CrossRefPubMed

183.

Nakamoto N, Amiya T, Aoki R, Taniki N, Koda Y, Miyamoto K, Teratani T, Suzuki T, Chiba S, Chu PS, Hayashi A, Yamaguchi A, Shiba S, Miyake R, Katayama T, Suda W, Mikami Y, Kamada N, Ebinuma H, Saito H, Hattori M, Kanai T (2017) Commensal lactobacillus controls immune tolerance during acute liver injury in mice. Cell Rep 21:1215–1226. https://doi.org/10.1016/j.celrep.2017.10.022 CrossRefPubMed

184.

Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L (2006) A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol 4:754–759. https://doi.org/10.1016/j.cgh.2006.03.028 CrossRefPubMed

185.

Mohrs M, Blankespoor CM, Wang ZE, Loots GG, Afzal V, Hadeiba H, Shinkai K, Rubin EM, Locksley RM (2001) Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat Immunol 2:842–847. https://doi.org/10.1038/ni0901-842 CrossRefPubMed

186.

Fields PE, Lee GR, Kim ST, Bartsevich VV, Flavell RA (2004) Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity 21:865–876. https://doi.org/10.1016/j.immuni.2004.10.015 CrossRefPubMed

187.

Takemoto N, Kamogawa Y, Jun Lee H, Kurata H, Arai KI, O'Garra A, Arai N, Miyatake S (2000) Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster. J Immunol 165:6687–6691CrossRefPubMed

188.

Loots GG, Locksley RM, Blankespoor CM, Wang ZE, Miller W, Rubin EM, Frazer KA (2000) Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288:136–140CrossRefPubMed

189.

Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117:515–526CrossRefPubMed

190.

Tanaka S, Motomura Y, Suzuki Y, Yagi R, Inoue H, Miyatake S, Kubo M (2011) The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells. Nat Immunol 12:77–85. https://doi.org/10.1038/ni.1966 CrossRefPubMed

191.

Yamashita M, Ukai-Tadenuma M, Kimura M, Omori M, Inami M, Taniguchi M, Nakayama T (2002) Identification of a conserved GATA3 response element upstream proximal from the interleukin-13 gene locus. J Biol Chem 277:42399–42408. https://doi.org/10.1074/jbc.M205876200 CrossRefPubMed

192.

Grausenburger R, Bilic I, Boucheron N, Zupkovitz G, El-Housseiny L, Tschismarov R, Zhang Y, Rembold M, Gaisberger M, Hartl A, Epstein MM, Matthias P, Seiser C, Ellmeier W (2010) Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol 185:3489–3497. https://doi.org/10.4049/jimmunol.0903610 CrossRefPubMed

193.

Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852. https://doi.org/10.1146/annurev.immunol.25.022106.141557 CrossRefPubMed

194.

Iwakura Y, Ishigame H (2006) The IL-23/IL-17 axis in inflammation. J Clin Invest 116:1218–1222. https://doi.org/10.1172/jci28508 CrossRefPubMedPubMedCentral

195.

Lee SJ, McLachlan JB, Kurtz JR, Fan D, Winter SE, Baumler AJ, Jenkins MK, McSorley SJ (2012) Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathog 8:e1002499. https://doi.org/10.1371/journal.ppat.1002499 CrossRefPubMedPubMedCentral

196.

Galvez J (2014) Role of Th17 cells in the pathogenesis of human IBD. ISRN Inflamm 2014:928461. https://doi.org/10.1155/2014/928461 CrossRefPubMedPubMedCentral

197.

Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, Kitazume MT, Nakazawa A, Sugita A, Koganei K, Isobe K, Hibi T (2008) IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57:1682–1689. https://doi.org/10.1136/gut.2007.135053 CrossRefPubMed

198.

Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T (2009) Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn’s disease. Gastroenterology 137:1736–1745. https://doi.org/10.1053/j.gastro.2009.07.049 CrossRefPubMed

199.

Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SP (2012) Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61:1693–1700. https://doi.org/10.1136/gutjnl-2011-301668 CrossRefPubMed

200.

Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949. https://doi.org/10.1038/ni1496 CrossRefPubMed

201.

Stritesky GL, Yeh N, Kaplan MH (2008) IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol 181:5948–5955CrossRefPubMed

202.

Rutz S, Noubade R, Eidenschenk C, Ota N, Zeng W, Zheng Y, Hackney J, Ding J, Singh H, Ouyang W (2011) Transcription factor c-Maf mediates the TGF-beta-dependent suppression of IL-22 production in T(H)17 cells. Nat Immunol 12:1238–1245. https://doi.org/10.1038/ni.2134 CrossRefPubMed

203.

Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, Agarwal A, Huang W, Parkhurst CN, Muratet M, Newberry KM, Meadows S, Greenfield A, Yang Y, Jain P, Kirigin FK, Birchmeier C, Wagner EF, Murphy KM, Myers RM, Bonneau R, Littman DR (2012) A validated regulatory network for Th17 cell specification. Cell 151:289–303. https://doi.org/10.1016/j.cell.2012.09.016 CrossRefPubMedPubMedCentral

204.

Wheaton JD, Yeh CH, Ciofani M (2017) Cutting edge: c-Maf is required for regulatory T cells to adopt RORgammat(+) and follicular phenotypes. J Immunol 199:3931–3936. https://doi.org/10.4049/jimmunol.1701134 CrossRefPubMed

205.

Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ, Galan C, Belkaid Y, Bonneau R, Littman DR (2018) C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554:373–377. https://doi.org/10.1038/nature25500 CrossRefPubMedPubMedCentral

206.

Tanaka S, Suto A, Iwamoto T, Kashiwakuma D, Kagami S, Suzuki K, Takatori H, Tamachi T, Hirose K, Onodera A, Suzuki J, Ohara O, Yamashita M, Nakayama T, Nakajima H (2014) Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORgammat induction as downstream targets of Stat3. J Exp Med 211:1857–1874. https://doi.org/10.1084/jem.20130791 CrossRefPubMedPubMedCentral

207.

Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057. https://doi.org/10.1038/nature07036 CrossRefPubMedPubMedCentral

208.

Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, Pouly S, Murphy AJ, Valenzuela DM, Yancopoulos GD, Becher B, Littman DR, Neurath MF (2009) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136:257–267. https://doi.org/10.1053/j.gastro.2008.10.018 CrossRefPubMed

209.

O'Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, Kolls JK, Flavell RA (2009) A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10:603–609. https://doi.org/10.1038/ni.1736 CrossRefPubMedPubMedCentral

210.

Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, Blumenschein WM, Judo M, Ayanoglu G, McClanahan TK, Li X, Cua DJ (2015) Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43:727–738. https://doi.org/10.1016/j.immuni.2015.09.003 CrossRefPubMedPubMedCentral

211.

Mikami Y, Kanai T, Sujino T, Ono Y, Hayashi A, Okazawa A, Kamada N, Matsuoka K, Hisamatsu T, Okamoto S, Takaishi H, Inoue N, Ogata H, Hibi T (2010) Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis. Eur J Immunol 40:2409–2422. https://doi.org/10.1002/eji.201040379 CrossRefPubMed

212.

Griseri T, Asquith M, Thompson C, Powrie F (2010) OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med 207:699–709. https://doi.org/10.1084/jem.20091618 CrossRefPubMedPubMedCentral

213.

Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, O'Connor W Jr, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA (2011) Control of TH17 cells occurs in the small intestine. Nature 475:514–518. https://doi.org/10.1038/nature10228 CrossRefPubMedPubMedCentral

214.

Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, Martin-Orozco N, Kang HS, Ma L, Panopoulos AD, Craig S, Watowich SS, Jetten AM, Tian Q, Dong C (2008) CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 181:8391–8401CrossRefPubMed

215.

Huber S, Gagliani N, Esplugues E, O'Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3(−) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34:554–565. https://doi.org/10.1016/j.immuni.2011.01.020 CrossRefPubMedPubMedCentral

216.

Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limon P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA (2015) Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523:221–225. https://doi.org/10.1038/nature14452 CrossRefPubMedPubMedCentral

217.

Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13:991–999. https://doi.org/10.1038/ni.2416 CrossRefPubMedPubMedCentral

218.

Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O'Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971. https://doi.org/10.1038/nature09447 CrossRefPubMedPubMedCentral

219.

Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, Pandolfi PP, Mak T, Satija R, Shalek AK, Kuchroo VK, Park H, Regev A (2015) Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 163:1400–1412. https://doi.org/10.1016/j.cell.2015.11.009 CrossRefPubMedPubMedCentral

220.

McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8:1390–1397. https://doi.org/10.1038/ni1539 CrossRefPubMed

221.

Liu HP, Cao AT, Feng T, Li Q, Zhang W, Yao S, Dann SM, Elson CO, Cong Y (2015) TGF-beta converts Th1 cells into Th17 cells through stimulation of Runx1 expression. Eur J Immunol 45:1010–1018. https://doi.org/10.1002/eji.201444726 CrossRefPubMedPubMedCentral

222.

Glauben R, Siegmund B (2011) Inhibition of histone deacetylases in inflammatory bowel diseases. Mol Med 17:426–433. https://doi.org/10.2119/molmed.2011.00069 CrossRefPubMedPubMedCentral

223.

Li X, Wu L, Corsa CA, Kunkel S, Dou Y (2009) Two mammalian MOF complexes regulate transcription activation by distinct mechanisms. Mol Cell 36:290–301. https://doi.org/10.1016/j.molcel.2009.07.031 CrossRefPubMedPubMedCentral

224.

Tsaprouni LG, Ito K, Powell JJ, Adcock IM, Punchard N (2011) Differential patterns of histone acetylation in inflammatory bowel diseases. J Inflamm (Lond) 8:1. https://doi.org/10.1186/1476-9255-8-1 CrossRef

225.

Yang Y, Guan J, Shaikh AS, Liang Y, Sun L, Wang M, Li D, Qiu C, Li X (2018) Histone acetyltransferase Mof affects the progression of DSS-induced colitis. Cell Physiol Biochem 47:2159–2169. https://doi.org/10.1159/000491527 CrossRefPubMed

226.

Zhang S, Takaku M, Zou L, Gu AD, Chou WC, Zhang G, Wu B, Kong Q, Thomas SY, Serody JS, Chen X, Xu X, Wade PA, Cook DN, Ting JPY, Wan YY (2017) Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 551:105–109. https://doi.org/10.1038/nature24283 CrossRefPubMedPubMedCentral

227.

Dallavalle S, Pisano C, Zunino F (2012) Development and therapeutic impact of HDAC6-selective inhibitors. Biochem Pharmacol 84:756–765. https://doi.org/10.1016/j.bcp.2012.06.014 CrossRefPubMed

228.

Salkowska A, Karas K, Walczak-Drzewiecka A, Dastych J, Ratajewski M (2017) Differentiation stage-specific effect of histone deacetylase inhibitors on the expression of RORgammaT in human lymphocytes. J Leukoc Biol 102:1487–1495. https://doi.org/10.1189/jlb.6A0617-217R CrossRefPubMed

229.

Glauben R, Sonnenberg E, Wetzel M, Mascagni P, Siegmund B (2014) Histone deacetylase inhibitors modulate interleukin 6-dependent CD4+ T cell polarization in vitro and in vivo. J Biol Chem 289:6142–6151. https://doi.org/10.1074/jbc.M113.517599 CrossRefPubMedPubMedCentral

230.

Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, Mascagni P, Fantuzzi G, Dinarello CA, Siegmund B (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176:5015–5022CrossRefPubMed

231.

Cosenza M, Pozzi S (2018) The therapeutic strategy of HDAC6 inhibitors in lymphoproliferative disease. Int J Mol Sci 19. https://doi.org/10.3390/ijms19082337

232.

Pei XF, Cao LL, Huang F, Qiao X, Yu J, Ye H, Xi CL, Zhou QC, Zhang GF, Gong ZL (2018) Role of miR-22 in intestinal mucosa tissues and peripheral blood CD4+ T cells of inflammatory bowel disease. Pathol Res Pract 214:1095–1104. https://doi.org/10.1016/j.prp.2018.04.009 CrossRefPubMed

233.

Lykken EA, Li QJ (2011) microRNAs at the regulatory frontier: an investigation into how microRNAs impact the development and effector functions of CD4 T cells. Immunol Res 49:87–96. https://doi.org/10.1007/s12026-010-8196-4 CrossRefPubMed

234.

Takagi T, Naito Y, Mizushima K, Hirata I, Yagi N, Tomatsuri N, Ando T, Oyamada Y, Isozaki Y, Hongo H, Uchiyama K, Handa O, Kokura S, Ichikawa H, Yoshikawa T (2010) Increased expression of microRNA in the inflamed colonic mucosa of patients with active ulcerative colitis. J Gastroenterol Hepatol 25(Suppl 1):S129–S133. https://doi.org/10.1111/j.1440-1746.2009.06216.x CrossRefPubMed

235.

Fasseu M, Treton X, Guichard C, Pedruzzi E, Cazals-Hatem D, Richard C, Aparicio T, Daniel F, Soule JC, Moreau R, Bouhnik Y, Laburthe M, Groyer A, Ogier-Denis E (2010) Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. PLoS One 5. https://doi.org/10.1371/journal.pone.0013160

236.

Hou J, Hu X, Chen B, Chen X, Zhao L, Chen Z, Liu F, Liu Z (2017) miR-155 targets Est-1 and induces ulcerative colitis via the IL-23/17/6-mediated Th17 pathway. Pathol Res Pract 213:1289–1295. https://doi.org/10.1016/j.prp.2017.08.001 CrossRefPubMed

237.

Singh UP, Murphy AE, Enos RT, Shamran HA, Singh NP, Guan H, Hegde VL, Fan D, Price RL, Taub DD, Mishra MK, Nagarkatti M, Nagarkatti PS (2014) miR-155 deficiency protects mice from experimental colitis by reducing T helper type 1/type 17 responses. Immunology 143:478–489. https://doi.org/10.1111/imm.12328 CrossRefPubMedPubMedCentral

238.

Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, Li Z, Wu Z, Pei G (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 10:1252–1259. https://doi.org/10.1038/ni.1798 CrossRefPubMed

239.

Ichiyama K, Gonzalez-Martin A, Kim BS, Jin HY, Jin W, Xu W, Sabouri-Ghomi M, Xu S, Zheng P, Xiao C, Dong C (2016) The MicroRNA-183-96-182 cluster promotes T helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression. Immunity 44:1284–1298. https://doi.org/10.1016/j.immuni.2016.05.015 CrossRefPubMedPubMedCentral

240.

Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu AM, Morton V, Sun MY, Jewell D, Coccia M, Harrison O, Maloy K, Schonefeldt S, Bornschein S, Liston A, Simmons A (2013) The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity 39:521–536. https://doi.org/10.1016/j.immuni.2013.08.035 CrossRefPubMed

241.

Wang H, Flach H, Onizawa M, Wei L, McManus MT, Weiss A (2014) Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210. Nat Immunol 15:393–401. https://doi.org/10.1038/ni.2846 CrossRefPubMedPubMedCentral

242.

Shih HY, Sciume G, Mikami Y, Guo L, Sun HW, Brooks SR, Urban JF Jr, Davis FP, Kanno Y, O'Shea JJ (2016) Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell 165:1120–1133. https://doi.org/10.1016/j.cell.2016.04.029 CrossRefPubMedPubMedCentral

Springer Medizin

Epigenetic regulation of T helper cells and intestinal pathogenicity

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Update Innere Medizin

Springer Medizin

Abstract

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