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Yonsei Med J. 2009 Jun;50(3):322-330.
Published online 2009 June 23.  doi: 10.3349/ymj.2009.50.3.322.
© Copyright: Yonsei University College of Medicine 2009
Epigenetic Regulation of Cytokine Gene Expression in T Lymphocytes
Choong-Gu Lee,* Anupama Sahoo,* and Sin-Hyeog Im
Department of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.

Corresponding author: Dr. Sin-Hyeog Im, Department of Life Sciences, Gwangju Institute of Science and Technology (GIST), 1 Oryong-dong, Buk-gu, Gwangju 500-712, Korea. Tel: 82-62-970-2503, Fax: 82-62-970-2484, Email: imsh@gist.ac.kr

*These authors contributed equally to this work.

Received May 08, 2009.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.

Keywords: Epigenetics, cytokine, T lymphocytes, gene regulation.
References
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. Min-Hao Kuo,CD Allis.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 Dec;: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.