Skip to main content

Epigenetic regulation of T helper cells and intestinal pathogenicity

Seminars in Immunopathology volume 41, pages 379–399 (2019)Cite this article

Abstract

Inflammatory bowel diseases (IBDs) are characterized by relapsing and remitting chronic intestinal inflammation. Previous studies have demonstrated the contributions of genetic background, environmental factors (food, microbiota, use of antibiotics), and host immunity in the development of IBDs. More than 200 genes have been shown to influence IBD susceptibility, most of which are involved in immunity. The vertebrate immune system comprises a complex network of innate and adaptive immune cells that protect the host from infection and cancer. Dysregulation of the mutualistic relationship between the immune system and the gut environment results in IBD. Considering the fundamental role of epigenetic regulation in immune cells, epigenetic mechanisms, particularly in T helper (Th) cells, may play a major role in the complex regulation of mucosal immunity. Epigenetic regulation and dysregulation of Th cells are involved in the maintenance of intestinal homeostasis and its breakdown in IBD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

AhR:

Aryl hydrocarbon receptor

Areg:

Amphiregulin

AP-1:

Activator protein 1

Ar5:

Accessible region 5

CD:

Crohn’s disease

CBFβ:

Core-binding factor, beta subunit

CNS:

Conserved non-coding sequence

CREB:

Cyclic adenosine monophosphate response element-binding protein

DC:

Dendritic cell

DNMT:

DNA-methyltransferase

DR3:

Death receptor 3

DSS:

Dextran sodium sulfate

EAE:

Experimental autoimmune encephalomyelitis

FOXO:

Forkhead box 0

GVHD:

Graft-versus-host disease

H3K4me3:

Histone 3 lysine 4 tri-methylation

H3K27Ac:

H3 lysine 27 acetylation

HAT:

Histone acethyltransferase

HDAC:

Histone deacetylase

HS:

Hypersensitive site

IBD:

Inflammatory bowel disease

IFN:

Interferon

IL:

Interleukin

IPEX:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

IRF4:

Interferon regulatory factor 4

LDTF:

Lineage-defining transcription factor

lncRNA:

Long non-coding RNA

LTβR:

Lymphotoxin β receptor

miRNA:

Micro RNA

miR-183C:

miR-183-96-182 cluster

mLN:

Mesenteric lymph node

MS:

Multiple sclerosis

NFAT:

Nuclear factor of activated T cells

NK:

Natural killer

OVA:

Ovalbumin

PCAF:

p300/CREB-binding protein-associated factor

PcGs:

Polycomb-group proteins

PRC:

Polycomb repressive complex

RA:

Retinoic acid

ROR:

Retinoic acid-related orphan receptor

SOCS:

Suppressor of cytokine signaling

T-bet:

T-box expressed in T

TCR:

T cell receptor

TET:

Ten-eleven translocation

TGF:

Transforming growth factor

Th:

Helper T

TNBS:

Trinitrobenzene sulfonic acid

TNF:

Tumor necrosis factor

Treg:

Regulatory T

TRUC:

T-bet−/− × RAG2−/−

UC:

Ulcerative colitis

TSDR:

Treg cell-specific demethylated region;

References

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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 128:1868–1878

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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 173:3119–3130

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 177:8338–8347

    CAS  Article  Google Scholar 

  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 181:2277–2284

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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 163:143–147

    CAS  PubMed  Google Scholar 

  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 162:6829–6835

    CAS  PubMed  Google Scholar 

  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 121:875–888

    CAS  Article  Google Scholar 

  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 121:1372–1379

    Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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 17:167–178

    CAS  Article  Google Scholar 

  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 10:371–378

    CAS  Article  Google Scholar 

  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 169:4850–4860

    Article  Google Scholar 

  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 178:280–290

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 195:71–84

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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 100:655–669

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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 75:843–854

    CAS  Article  Google Scholar 

  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 75:855–862

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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 77:5632–5638

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 9:423–432

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  Google Scholar 

  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 33:435–440

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    Google Scholar 

  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 119:1473–1482

    CAS  Article  Google Scholar 

  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 119:1461–1472

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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 165:6687–6691

    CAS  Article  Google Scholar 

  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 288:136–140

    CAS  Article  Google Scholar 

  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 117:515–526

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 181:8391–8401

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 176:5015–5022

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (A) 15H02534 and Grant-in-Aid for Young Scientists (B) 17K15966; Advanced Research and Development Programs for Medical Innovation (AMED-CREST; 16gm1010003h0001 and 18gm1210001h0001); the Takeda Science Foundation; the Kanae Foundation for The Promotion of Medical Science; and Keio University Medical Fund.

Author information

Author notes

  1. Yuya Hagihara, Yusuke Yoshimatsu and Yohei Mikami contributed equally to this work.

Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuya Hagihara, Yusuke Yoshimatsu, Yohei Mikami, Yoshiaki Takada, Shinta Mizuno & Takanori Kanai

  2. AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan

    Takanori Kanai

Authors
  1. Yuya Hagihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yusuke Yoshimatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yohei Mikami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiaki Takada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinta Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takanori Kanai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yohei Mikami.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is a contribution to the special issue on The Pathogenicity of Acquired Immunity in Human Diseases - Guest Editor: Kiyoshi Hirahara

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hagihara, Y., Yoshimatsu, Y., Mikami, Y. et al. Epigenetic regulation of T helper cells and intestinal pathogenicity. Semin Immunopathol 41, 379–399 (2019). https://doi.org/10.1007/s00281-019-00732-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-019-00732-9

Keywords

  • CD4 T cell
  • Colitis
  • Mucosal immunology
  • Inflammatory bowel disease
  • Epigenetic regulation