Skip to main content
SpringerLink
Log in

Regulation of T cell differentiation and function by epigenetic modification enzymes

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Peripheral naive CD4+ and CD8+ cells are developed in the thymus and proliferate and differentiate into various specialized T cell subsets upon activation by peptide-major histocompatibility complexes in periphery to execute different functions during immune responses. Cytokines, transcription factors, and a large number of intracellular molecules have been shown to affect T cell development, activation, and function. In addition, epigenetic modifications, such as histone modification and DNA methylation, regulate T cell biology. The epigenetic modifications are regulated by a range of DNA methyltransferases, DNA demethylation enzymes, and histone modification enzymes. Dysregulations of epigenetic modifications are closely associated with autoimmune diseases and tumorigenesis. Here, we review the current literature about the functions of DNA and histone modification enzymes in T cell development, activation, differentiation, and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Veiga-Fernandes H, Walter U, Bourgeois C, McLean A, Rocha B (2000) Response of naive and memory CD8(+) T cells to antigen stimulation in vivo. Nat Immunol 1(1):47–53

    Article  CAS  PubMed  Google Scholar 

  2. Nakayamada S, Takahashi H, Kanno Y, O'Shea JJ (2012) Helper T cell diversity and plasticity. Curr Opin Immunol 24(3):297–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhu JF, Paul WE (2010) Heterogeneity and plasticity of T helper cells. Cell Res 20(1):4–12

    Article  CAS  PubMed  Google Scholar 

  4. Doherty PC, Topham DJ, Tripp RA (1996) Establishment and persistence of virus-specific CD4+ and CD8+ T cell memory. Immunol Rev 150:23–44

    Article  CAS  PubMed  Google Scholar 

  5. Agnello D, Lankford CSR, Bream J et al (2003) Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol 23(3):147–161

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(8):597–610

    Article  CAS  PubMed  Google Scholar 

  8. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705

    Article  CAS  PubMed  Google Scholar 

  9. Marmorstein R, Trievel RC (2009) Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta 1789(1):58–68

    Article  CAS  PubMed  Google Scholar 

  10. Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, van Calcar S, Qu C, Ching KA, Wang W, Weng Z, Green RD, Crawford GE, Ren B (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39(3):311–318

    Article  CAS  PubMed  Google Scholar 

  11. Pekowska A, Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F, Holota H, Imbert J, Andrau JC, Ferrier P, Spicuglia S (2011) H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J 30(20):4198–4210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR (2012) Landscape of transcription in human cells. Nature 489(7414):101–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257

    Article  CAS  PubMed  Google Scholar 

  14. Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9(16):2395–2402

    Article  CAS  PubMed  Google Scholar 

  15. Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, Pérez-Melgosa M, Sweetser MT, Schlissel MS, Nguyen S, Cherry SR, Tsai JH, Tucker SM, Weaver WM, Kelso A, Jaenisch R, Wilson CB (2001) A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15(5):763–774

    Article  CAS  PubMed  Google Scholar 

  16. Lee DU, Agarwal S, Rao A (2002) Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity 16(5):649–660

    Article  CAS  PubMed  Google Scholar 

  17. Wang LQ, Liu YJ, Beier UH et al (2013) Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood 121(18):3631–3639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pham D, Yu Q, Walline CC, Muthukrishnan R, Blum JS, Kaplan MH (2013) Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. J Immunol 191(2):902–911

    Article  CAS  PubMed  Google Scholar 

  19. Yu Q, Zhou BH, Zhang YL et al (2012) DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. Proc Natl Acad Sci U S A 109(2):541–546

    Article  PubMed  Google Scholar 

  20. Ladle BH, Li KP, Phillips MJ, Pucsek AB, Haile A, Powell JD, Jaffee EM, Hildeman DA, Gamper CJ (2016) De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation. Proc Natl Acad Sci U S A 113(38):10631–10636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Youngblood B, Hale JS, Kissick HT, Ahn E, Xu X, Wieland A, Araki K, West EE, Ghoneim HE, Fan Y, Dogra P, Davis CW, Konieczny BT, Antia R, Cheng X, Ahmed R (2017) Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552(7685):404–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu XJ, Zhang Y (2017) TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 18(9):517–534

    Article  CAS  PubMed  Google Scholar 

  23. Ooi SKT, O'Donnell AH, Bestor TH (2009) Mammalian cytosine methylation at a glance. J Cell Sci 122(16):2787–2791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tsagaratou A, Aijo T, Lio CWJ, Yue X, Huang Y, Jacobsen SE, Lahdesmaki H, Rao A (2014) Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc Natl Acad Sci U S A 111(32):E3306–E3315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Iyer LM, Tahiliani M, Rao A, Aravind L (2009) Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8(11):1698–1710

    Article  CAS  PubMed  Google Scholar 

  26. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8(2):200–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pastor WA, Aravind L, Rao A (2013) TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14(6):341–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yue XJ, Trifari S, Aijo T et al (2016) Control of Foxp3 stability through modulation of TET activity. J Exp Med 213(3):377–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nair VS, Oh KI (2014) Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells. Biochem Biophys Res Commun 450(1):918–924

    Article  CAS  PubMed  Google Scholar 

  30. Yang RL, Qu CY, Zhou Y et al (2015) Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity 43(2):251–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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(7282):808–U120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Floess S, Freyer J, Siewert C et al (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5(2):169–178

    Article  CAS  Google Scholar 

  33. Tsagaratou A, Gonzalez-Avalos E, Rautio S et al (2017) TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. Nat Immunol 18(1):45–53

    Article  CAS  PubMed  Google Scholar 

  34. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A (2011) Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A 108(35):14566–14571

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nair VS, Song MH, Oh KI (2016) Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J Immunol 196(5):2119–2131

    Article  CAS  Google Scholar 

  36. Marmorstein R, Zhou MM (2014) Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol 6(7)

  37. Ellmeier W, Seiser C (2018) Histone deacetylase function in CD4(+) T cells. Nat Rev Immunol 18:617–634

    Article  CAS  PubMed  Google Scholar 

  38. Harlow E, Whyte P, Franza BR Jr, Schley C (1986) Association of adenovirus early-region 1A proteins with cellular polypeptides. Mol Cell Biol 6(5):1579–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kasper LH, Fukuyama T, Biesen MA, Boussouar F, Tong C, de Pauw A, Murray PJ, van Deursen JMA, Brindle PK (2006) Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development. Mol Cell Biol 26(3):789–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Avots A, Buttmann M, Chuvpilo S, Escher C, Smola U, Bannister AJ, Rapp UR, Kouzarides T, Serfling E (1999) CBP/p300 integrates Raf/Rac-signaling pathways in the transcriptional induction of NF-ATc during T cell activation. Immunity 10(5):515–524

    Article  CAS  PubMed  Google Scholar 

  41. Hosokawa H, Tanaka T, Suzuki Y, Iwamura C, Ohkubo S, Endoh K, Kato M, Endo Y, Onodera A, Tumes DJ, Kanai A, Sugano S, Nakayama T (2013) Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity. Proc Natl Acad Sci U S A 110(12):4691–4696

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T-reg balance by hypoxia-inducible factor 1. Cell 146(5):772–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hammitzsch A, Tallant C, Fedorov O, O’Mahony A, Brennan PE, Hay DA, Martinez FO, al-Mossawi MH, de Wit J, Vecellio M, Wells C, Wordsworth P, Müller S, Knapp S, Bowness P (2015) CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci U S A 112(34):10768–10773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maekawa Y, Minato Y, Ishifune C, Kurihara T, Kitamura A, Kojima H, Yagita H, Sakata-Yanagimoto M, Saito T, Taniuchi I, Chiba S, Sone S, Yasutomo K (2008) Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat Immunol 9(10):1140–1147

    Article  CAS  PubMed  Google Scholar 

  45. van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YYJ, 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(5):965–974

    Article  CAS  PubMed  Google Scholar 

  46. Liu YJ, Wang LQ, Predina J et al (2013) Inhibition of p300 impairs Foxp3(+) T regulatory cell function and promotes antitumor immunity. Nat Med 19(9):1173–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SCJ, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O’Shea JJ (2015) Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520(7548):558–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Javaid N, Choi S (2017) Acetylation- and methylation-related epigenetic proteins in the context of their targets. Genes-Basel 8(8)

  49. Gao BX, Kong QF, Zhang YN et al (2017) The histone acetyltransferase Gcn5 positively regulates T cell activation. J Immunol 198(10):3927–3938

    Article  CAS  PubMed  Google Scholar 

  50. Goswami R, Kaplan MH (2012) Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol 189(6):3026–3033

    Article  CAS  PubMed  Google Scholar 

  51. Lee KK, Workman JL (2007) Histone acetyltransferase complexes: one size doesn't fit all. Nat Rev Mol Cell Biol 8(4):284–295

    Article  CAS  PubMed  Google Scholar 

  52. Millard CJ, Watson PJ, Fairall L, Schwabe JWR (2017) Targeting class I histone deacetylases in a “complex” environment. Trends Pharmacol Sci 38(4):363–377

    Article  CAS  PubMed  Google Scholar 

  53. Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM, Singh R, Vassiliou G, Bradley A, Cowley SM (2013) Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice. Blood 121(8):1335–1344

    Article  CAS  PubMed  Google Scholar 

  54. Boucheron N, Tschismarov R, Goeschl L et al (2014) CD4(+) T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. Nat Immunol 15(5):439–43+

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Goschl L, Preglej T, Hamminger P et al (2018) A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis. J Autoimmun 86:51–61

    Article  CAS  PubMed  Google Scholar 

  56. 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(6):3489–3497

    Article  CAS  PubMed  Google Scholar 

  57. Woods DM, Woan KV, Cheng FD et al (2017) T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 130(2):146–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yan KL, Cao Q, Reilly CM et al (2011) Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J Biol Chem 286(33):28833–28843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lim HW, Kang SG, Ryu JK, Schilling B, Fei M, Lee IS, Kehasse A, Shirakawa K, Yokoyama M, Schnölzer M, Kasler HG, Kwon HS, Gibson BW, Sato H, Akassoglou K, Xiao C, Littman DR, Ott M, Verdin E (2015) SIRT1 deacetylates ROR gamma t and enhances Th17 cell generation. J Exp Med 212(5):607–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang JN, Lee SM, Shannon S et al (2009) The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119(10):3048–3058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lu L, Barbi J, Pan F (2017) The regulation of immune tolerance by FOXP3. Nat Rev Immunol 17(11):703–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li B, Greene MI (2007) FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. Cell Cycle 6(12):1432–1436

    Article  CAS  PubMed  Google Scholar 

  63. Tao R, de Zoeten EF, Ozkaynak E et al (2007) Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13(11):1299–1307

    Article  CAS  PubMed  Google Scholar 

  64. Wang LQ, Liu YJ, Han RX et al (2015) FOXP3(+) regulatory T cell development and function require histone/protein deacetylase 3. J Clin Invest 125(3):1111–1123

    Article  PubMed  PubMed Central  Google Scholar 

  65. Shilatifard A (2006) Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75:243–269

    Article  CAS  PubMed  Google Scholar 

  66. Morera L, Lubbert M, Jung M (2016) Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics 8:57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16(14):1779–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Verbaro DJ, Sakurai N, Kim B, Shinkai Y, Egawa T (2018) Cutting edge: the histone methyltransferase G9a is required for silencing of helper T lineage-associated genes in proliferating CD8 T cells. J Immunol 200(12):3891–3896

    Article  CAS  PubMed  Google Scholar 

  69. Shin HM, Kapoor V, Guan T et al (2013) Epigenetic modifications induced by Blimp-1 regulate CD8(+) T cell memory progression during acute virus infection. Immunity 39(4):661–675

    Article  CAS  PubMed  Google Scholar 

  70. Hedrich CM, Crispin JC, Rauen T et al (2014) cAMP responsive element modulator (CREM) alpha mediates chromatin remodeling of CD8 during the generation of CD3(+)CD4(−)CD8(−) T cells. J Biol Chem 289(4):2361–2370

    Article  CAS  PubMed  Google Scholar 

  71. Antignano F, Burrows K, Hughes MR, Han JM, Kron KJ, Penrod NM, Oudhoff MJ, Wang SKH, Min PH, Gold MJ, Chenery AL, Braam MJS, Fung TC, Rossi FMV, McNagny KM, Arrowsmith CH, Lupien M, Levings MK, Zaph C (2014) Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. J Clin Invest 124(5):1945–1955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lehnertz B, Northrop JP, Antignano F, Burrows K, Hadidi S, Mullaly SC, Rossi FMV, Zaph C (2010) Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J Exp Med 207(5):915–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang XH, Cook PC, Zindy E et al (2016) Integrin alpha 4 beta 1 controls G9a activity that regulates epigenetic changes and nuclear properties required for lymphocyte migration. Nucleic Acids Res 44(7):3031–3044

    Article  CAS  PubMed  Google Scholar 

  74. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410(6824):120–124

    Article  CAS  PubMed  Google Scholar 

  75. Wakabayashi Y, Tamiya T, Takada I, Fukaya T, Sugiyama Y, Inoue N, Kimura A, Morita R, Kashiwagi I, Takimoto T, Nomura M, Yoshimura A (2011) Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-beta-Smad pathway. J Biol Chem 286(41):35456–35465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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(7406):249–U137

    Article  CAS  PubMed  Google Scholar 

  77. Pace L, Goudot C, Zueva E, Gueguen P, Burgdorf N, Waterfall JJ, Quivy JP, Almouzni G, Amigorena S (2018) The epigenetic control of stemness in CD8(+) T cell fate commitment. Science 359(6372):177–17+

    Article  CAS  PubMed  Google Scholar 

  78. Morey L, Helin K (2010) Polycomb group protein-mediated repression of transcription. Trends Biochem Sci 35(6):323–332

    Article  CAS  PubMed  Google Scholar 

  79. Yang XP, Jiang K, Hirahara K et al (2015) EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep-Uk 5

  80. 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(5):819–832

    Article  CAS  PubMed  Google Scholar 

  81. DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, Marson A, Bluestone JA (2015) The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity 42(2):227–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhang YX, Kinkel S, Maksimovic J et al (2014) The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 124(5):737–749

    Article  CAS  PubMed  Google Scholar 

  83. Su I, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, Marqueron R, Viale A, Reinberg D, Wülfing C, Tarakhovsky A (2005) Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121(3):425–436

    Article  CAS  PubMed  Google Scholar 

  84. Gray SM, Amezquita RA, Guan TX et al (2017) Polycomb repressive complex 2-mediated chromatin repression guides effector CD8(+) T cell terminal differentiation and loss of multipotency. Immunity 46(4):596–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. He S, Liu YN, Meng LJ et al (2017) Ezh2 phosphorylation state determines its capacity to maintain CD8(+) T memory precursors for antitumor immunity. Nat Commun 8:2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, Kotarski J, Tarkowski R, Dou Y, Cho K, Hensley-Alford S, Munkarah A, Liu R, Zou W (2015) Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527(7577):249–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Goswami S, Apostolou I, Zhang J, Skepner J, Anandhan S, Zhang X, Xiong L, Trojer P, Aparicio A, Subudhi SK, Allison JP, Zhao H, Sharma P (2018) Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest 128(9):3813–3818

    Article  PubMed  PubMed Central  Google Scholar 

  88. Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, Dubois G, Mazo A, Croce CM, Canaani E (2002) ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell 10(5):1119–1128

    Article  CAS  PubMed  Google Scholar 

  89. Yamashita M, Hirahara K, Shinnakasu R, Hosokawa H, Norikane S, Kimura MY, Hasegawa A, Nakayama T (2006) Crucial role of MLL for the maintenance of memory T helper type 2 cell responses. Immunity 24(5):611–622

    Article  CAS  PubMed  Google Scholar 

  90. Schaller M, Ito T, Allen RM, Kroetz D, Kittan N, Ptaschinski C, Cavassani K, Carson WF, Godessart N, Grembecka J, Cierpicki T, Dou Y, Kunkel SL (2015) Epigenetic regulation of IL-12-dependent T cell proliferation. J Leukoc Biol 98(4):601–613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Placek K, Hu GQ, Cui KR et al (2017) MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping. Nat Immunol 18(9):1035–103+

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hong SH, Cho YW, Yu LR et al (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A 104(47):18439–18444

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wang CC, Lee JE, Cho YW et al (2012) UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci U S A 109(38):15324–15329

    Article  PubMed  PubMed Central  Google Scholar 

  94. Manna S, Kim JK, Bauge C et al (2015) Histone H3 lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation. Nat Commun 6:8152

    Article  PubMed  Google Scholar 

  95. Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, Loizou E, Holmfeldt L, Strikoudis A, King B, Mullenders J, Becksfort J, Nedjic J, Paietta E, Tallman MS, Rowe JM, Tonon G, Satoh T, Kruidenier L, Prinjha R, Akira S, van Vlierberghe P, Ferrando AA, Jaenisch R, Mullighan CG, Aifantis I (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514(7523):513–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Li QT, Zou J, Wang MJ et al (2014) Critical role of histone demethylase Jmjd3 in the regulation of CD4(+) T-cell differentiation. Nat Commun 5:5780

    Article  CAS  PubMed  Google Scholar 

  97. Liu Z, Cao W, Xu LX et al (2015) The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. J Mol Cell Biol 7(6):505–516

    Article  CAS  PubMed  Google Scholar 

  98. Wang XH, Zhang YB, Yang XXO et al (2012) Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity 36(1):23–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors apologize to colleagues for works that were uncited due to space constrains. This work was supported by grants from the National Scientific Foundation of China to X.P.Y (81671539, 31470851, and 31870892) and to H.B.L (81725004).

Author information

Authors and Affiliations

  1. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Huicheng Liu, Pingfei Li, Zhengping Wei, Cai Zhang, Minghui Xia, Qiuyang Du, Yufei Chen, Na Liu & Xiang-Ping Yang

  2. Department of Immunology, Hubei University of Medicine, Shiyan, 442000, China

    Pingfei Li

  3. Department of Otolaryngology-Head and Neck Surgery, Center for Allergic and Inflammatory Diseases, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, 200031, China

    Huabin Li

Authors
  1. Huicheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pingfei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengping Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Minghui Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiuyang Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yufei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Na Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huabin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiang-Ping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiang-Ping Yang.

Ethics declarations

Competing interests

The authors declare no competing financial or non-financial interests.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, H., Li, P., Wei, Z. et al. Regulation of T cell differentiation and function by epigenetic modification enzymes. Semin Immunopathol 41, 315–326 (2019). https://doi.org/10.1007/s00281-019-00731-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-019-00731-w

Keywords

Search

Navigation