Yonsei Med J.  2009 Jun;50(3):322-330. 10.3349/ymj.2009.50.3.322.

Epigenetic Regulation of Cytokine Gene Expression in T Lymphocytes

• Lee CG
• Sahoo A
• Im SH

• KMID: 1758557
• DOI: http://doi.org/10.3349/ymj.2009.50.3.322

Abstract

The developmental program of T helper and regulatory T cell lineage commitment is governed by both genetic and epigenetic mechanisms. The principal events, signaling pathways and the lineage determining factors involved have been extensively studied in the past ten years. Recent studies have elucidated the important role of chromatin remodeling and epigenetic changes for proper regulation of gene expression of lineage-specific cytokines. These include DNA methylation and histone modifications in epigenomic reprogramming during T helper cell development and effector T cell functions. This review discusses the basic epigenetic mechanisms and the role of transcription factors for the differential cytokine gene regulation in the T helper lymphocyte subsets.

Keyword

Epigenetics; cytokine; T lymphocytes; gene regulation

MeSH Terms

Animals
Cytokines/metabolism
Epigenesis, Genetic/*genetics
Gene Expression Regulation/genetics/physiology
Humans
T-Lymphocytes/*metabolism

Figure

• 

  Fig. 1 Diversification of naïve CD4 + T helper cells into various effector T helper cell lineages. Upon antigenic stimulation, naïve CD4 + T cells can be differentiated into diverse T helper cell subsets like Th1, Th2, Th17 and Treg. From in vitro and in vivo studies, instructive cytokines and transcription factors which are specific for each effector lineage were identified. In the early initiation stage, the unique signal transducer and activator of transcription (STAT) is activated by the environmental cytokine signals which leads to induction of lineage master regulators. Transcription factors from each distinct subset activate and control the various downstream genes and this mechanism is further enhanced and stabilizes the lineage commitment with epigenetic modification by specific stimuli and the action of transcription factors. As a result, effector cytokines and modulators can be released from each CD4 + T helper cell subsets and these further regulate immune responses accordingly to antigens.

• 

  Fig. 2 Epigenetic modifications in T helper cells. Histone modifications and DNA methylation are two major epigenetic mechanisms which governs gene expression in mammalian cells. First, DNA methylation is detected from the 5-cytosine of CpG dinucleotides or CpG islands which is generally associated with the mechanism of gene silencing. Posttranslational modification of histone molecules occurs mainly at H4 or H4 tails. Histone tails are easily modified by the external stimuli and consist of various types of modifications such as acetylation, methylation, phosphorylation, and sumoylation. Among these, acetylation and methylation on lysine residues are well known representative modifications during T helper cell differentiation. Level of acetylation and lysine 4 methylation of Histone H3 and H4 are generally linked with active and accessible state of gene regulation while methylation of lysine 9 and 27 are well known marks of silent or inactive gene regulation.

Reference

1. Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol. 2003. 4:616–623.

2. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. Development of TH1 CD4 + T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993. 260:547–549.

3. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature. 1996. 382:174–177.

4. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996. 382:171–174.

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

6. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 2002. 295:338–342.

7. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol. 2002. 3:549–557.

8. Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, et al. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci U S A. 2001. 98:15137–15142.

9. Shi M, Lin TH, Appell KC, Berg LJ. Janus-kinase-3-dependent signals induce chromatin remodeling at the lfng locus during T helper 1 cell differentiation. Immunity. 2008. 28:763–773.

10. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996. 383:787–793.

11. Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell. 1994. 76:241–251.

12. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol. 1994. 12:227–257.

13. Sher A, Coffman RL. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu Rev Immunol. 1992. 10:385–409.

14. Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990. 145:3796–3806.

15. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996. 4:313–319.

16. Kurata H, Lee HJ, O'Garra A, Arai N. Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity. 1999. 11:677–688.

17. Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O'Garra A, et al. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med. 2000. 192:105–115.

18. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996. 380:630–633.

19. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996. 380:627–630.

20. Kim JI, Ho IC, Grusby MJ, Glimcher LH. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity. 1999. 10:745–751.

21. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005. 201:233–240.

22. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006. 126:1121–1133.

23. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007. 282:9358–9363.

24. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008. 28:29–39.

25. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008. 28:454–467.

26. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995. 155:1151–1164.

27. Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 2000. 101:455–458.

28. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005. 6:331–337.

29. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003. 299:1057–1061.

30. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001. 27:68–73.

31. Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol. 2003. 15:430–435.

32. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001. 182:68–79.

33. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006. 212:28–50.

34. Weiner HL. Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes Infect. 2001. 3:947–954.

35. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002. 16:6–21.

36. Illingworth R, Kerr A, Desousa D, Jørgensen H, Ellis P, Stalker J, et al. A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol. 2008. 6:e22.

37. Miranda TB, Jones PA. DNA methylation: the nuts and bolts of repression. J Cell Physiol. 2007. 213:384–390.

38. Delcuve GP, Rastegar M, Davie JR. Epigenetic control. J Cell Physiol. 2009. 219:243–250.

39. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002. 3:662–673.

40. Feng Q, Zhang Y. The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes Dev. 2001. 15:827–832.

41. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998. 19:187–191.

42. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998. 393:386–388.

43. Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999. 23:58–61.

44. Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 1999. 13:1924–1935.

45. Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003. 4:235–240.

46. Ooi SK, Bestor TH. The colorful history of active DNA demethylation. Cell. 2008. 133:1145–1148.

47. Kouzarides T. Chromatin modifications and their function. Cell. 2007. 128:693–705.

48. Munshi A, Shafi G, Aliya N, Jyothy A. Histone modifications dictate specific biological readouts. J Genet Genomics. 2009. 36:75–88.

49. Kuo Min-Hao, Allis CD. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays. 1998. 20:615–626.

50. Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem. 2001. 70:81–120.

51. Robinson PJ, An W, Routh A, Martino F, Chapman L, Roeder RG, et al. 30 nm chromatin fibre decompaction requires both H4-K16 acetylation and linker histone eviction. J Mol Biol. 2008. 381:816–825.

52. Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007. 447:407–412.

53. Jenuwein T, Allis CD. Translating the histone code. Science. 2001. 293:1074–1080.

54. Jenuwein T. Re-SET-ting heterochromatin by histone methyltransferases. Trends Cell Biol. 2001. 11:266–273.

55. Cosgrove MS, Boeke JD, Wolberger C. Regulated nucleosome mobility and the histone code. Nat Struct Mol Biol. 2004. 11:1037–1043.

56. Cosgrove MS, Wolberger C. How does the histone code work? Biochem Cell Biol. 2005. 83:468–476.

57. Peterson CL, Laniel MA. Histones and histone modifications. Curr Biol. 2004. 14:R546–R551.

58. Sims RJ 3rd, Reinberg D. Histone H3 Lys 4 methylation: caught in a bind? Genes Dev. 2006. 20:2779–2786.

59. Strähle U, Rastegar S. Conserved non-coding sequences and transcriptional regulation. Brain Res Bull. 2008. 75:225–230.

60. Janson PC, Winerdal ME, Winqvist O. At the crossroads of T helper lineage commitment-Epigenetics points the way. Biochim Biophys Acta. 2008. 12. 30. [Epub ahead of print].

61. Kadonaga JT. Regulation of RNA polymerase II transcription by sequence-specific DNA binding factors. Cell. 2004. 116:247–257.

62. Hardison RC. Conserved noncoding sequences are reliable guides to regulatory elements. Trends Genet. 2000. 16:369–372.

63. Lee GR, Fields PE, Griffin TJ, Flavell RA. Regulation of the Th2 cytokine locus by a locus control region. Immunity. 2003. 19:145–153.

64. West AG, Fraser P. Remote control of gene transcription. Hum Mol Genet. 2005. 14:R101–R111.

65. Grogan JL, Mohrs M, Harmon B, Lacy DA, Sedat JW, Locksley RM. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity. 2001. 14:205–215.

66. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A. T (H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol. 2002. 3:643–651.

67. Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002. 2:933–944.

68. Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, et al. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol. 2007. 8:732–742.

69. Jones B, Chen J. Inhibition of IFN-gamma transcription by site-specific methylation during T helper cell development. EMBO J. 2006. 25:2443–2452.

70. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity. 1998. 9:765–775.

71. Lee DU, Avni O, Chen L, Rao A. A distal enhancer in the interferon-gamma (IFN-gamma) locus revealed by genome sequence comparison. J Biol Chem. 2004. 279:4802–4810.

72. Shnyreva M, Weaver WM, Blanchette M, Taylor SL, Tompa M, Fitzpatrick DR, et al. Evolutionarily conserved sequence elements that positively regulate IFN-gamma expression in T cells. Proc Natl Acad Sci U S A. 2004. 101:12622–12627.

73. Chang S, Aune TM. Dynamic changes in histone-methylation 'marks' across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat Immunol. 2007. 8:723–731.

74. Zhang F, Boothby M. T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-gamma promoter are Stat4 dependent. J Exp Med. 2006. 203:1493–1505.

75. Fields PE, Kim ST, Flavell RA. Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation. J Immunol. 2002. 169:647–650.

76. Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science. 2001. 292:1907–1910.

77. Tong Y, Aune T, Boothby M. T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-gamma promoter via a conserved T-box half-site. Proc Natl Acad Sci U S A. 2005. 102:2034–2039.

78. Miller SA, Huang AC, Miazgowicz MM, Brassil MM, Weinmann AS. Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev. 2008. 22:2980–2993.

79. Lee GR, Kim ST, Spilianakis CG, Fields PE, Flavell RA. T helper cell differentiation: regulation by cis elements and epigenetics. Immunity. 2006. 24:369–379.

80. Bird JJ, Brown DR, Mullen AC, Moskowitz NH, Mahowald MA, Sider JR, et al. Helper T cell differentiation is controlled by the cell cycle. Immunity. 1998. 9:229–237.

81. Hutchins AS, Mullen AC, Lee HW, Sykes KJ, High FA, Hendrich BD, et al. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002. 10:81–91.

82. Fields PE, Lee GR, Kim ST, Bartsevich VV, Flavell RA. Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity. 2004. 21:865–876.

83. Lee DU, Rao A. Molecular analysis of a locus control region in the T helper 2 cytokine gene cluster: a target for STAT6 but not GATA3. Proc Natl Acad Sci U S A. 2004. 101:16010–16015.

84. Baguet A, Bix M. Chromatin landscape dynamics of the Il4-Il13 locus during T helper 1 and 2 development. Proc Natl Acad Sci U S A. 2004. 101:11410–11415.

85. Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, Bix M. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem. 2005. 280:31470–31477.

86. Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol. 2009. 9:91–105.

87. Jones EA, Flavell RA. Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster. J Immunol. 2005. 175:7437–7446.

88. Lee CG, Kang KH, So JS, Kwon HK, Son JS, Song MK, et al. A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol Immunol. 2008. 46:613–621.

89. Im SH, Hueber A, Monticelli S, Kang KH, Rao A. Chromatin-level regulation of the IL 10 gene in T cells. J Biol Chem. 2004. 279:46818–46825.

90. Wang ZY, Sato H, Kusam S, Sehra S, Toney LM, Dent AL. Regulation of IL-10 gene expression in Th2 Cells by Jun proteins. J Immunol. 2005. 174:2098–2105.

91. Chang HD, Helbig C, Tykocinski L, Kreher S, Koeck J, Niesner U, et al. Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur J Immunol. 2007. 37:807–817.

92. Shoemaker J, Saraiva M, O'Garra A. GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J Immunol. 2006. 176:3470–3479.

93. Ivanov II, Zhou L, Littman DR. Transcriptional regulation of Th17 cell differentiation. Semin Immunol. 2007. 19:409–417.

94. Akimzhanov AM, Yang XO, Dong C. Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem. 2007. 282:5969–5972.

95. Wei L, Laurence A, Elias KM, O'Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem. 2007. 282:34605–34610.

96. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007. 5:e38.

97. Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med. 2007. 204:1543–1551.

98. Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008. 38:1654–1663.

99. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009. 182:259–273.

100. Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol. 2007. 9:194–202.