Helper T-cell identity and evolution of differential transcriptomes and epigenomes

Immunological Reviews

Volumn 252, Issue 1, 2013, Pages 24-40

  Vahedi, Golnaz ^a   C Poholek, Amanda ^a   Hand, Timothy W ^b   Laurence, Arian ^a   Kanno, Yuka ^a   O'Shea, John J ^a   Hirahara, Kiyoshi ^a  

^a NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES   (United States)

^b NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

Enhancers; Epigenetics; Histone modification; Master regulator; STAT; T cell differentiation; T cell plasticity

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 4; PROTEIN BCL 6; STAT PROTEIN; STAT3 PROTEIN; STAT4 PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTOME; TRANSFORMING GROWTH FACTOR BETA;

ARTICLE; CD4+ T LYMPHOCYTE; CELL FATE; CELLULAR IMMUNITY; CHROMATIN; EPIGENETICS; GENE EXPRESSION; HELPER CELL; HISTONE MODIFICATION; HUMAN; LYMPHOCYTE DIFFERENTIATION; NONHUMAN; PLASTICITY; PRIORITY JOURNAL; PROGENY; PROMOTER REGION; RNA SEQUENCE; TH17 CELL;

EID: 84873620273     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12037     Document Type: Article

References (218)

1. Bulger M, Groudine M. Functional and mechanistic diversity of distal transcription enhancers. Cell 2011;144:327-339.
2. Djebali S, et al. Landscape of transcription in human cells. Nature 2012;489:101-108.
3. Natoli G. Maintaining cell identity through global control of genomic organization. Immunity 2010;33:12-24.
4. Maston GA, Evans SK, Green MR. Transcriptional regulatory elements in the human genome. Annu Rev Genomics Hum Genet 2006;7:29-59.
5. Prabhakar S, Noonan JP, Paabo S, Rubin EM. Accelerated evolution of conserved noncoding sequences in humans. Science 2006;314:786.
6. Buecker C, Wysocka J. Enhancers as information integration hubs in development: lessons from genomics. Trends Genet 2012;28:276-284.
7. Gross DS, Garrard WT. Nuclease hypersensitive sites in chromatin. Annu Rev Biochem 1988;57:159-197.
8. Thurman RE, et al. The accessible chromatin landscape of the human genome. Nature 2012;489:75-82.
9. Creyghton MP, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 2010;107:21931-21936.
10. Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 2011;470:279-283.
11. Visel A, et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 2009;457:854-858.
12. Wang D, et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 2011;474:390-397.
13. Kim TK, et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 2010;465:182-187.
14. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145-173.
15. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787-793.
16. Stockinger B, Veldhoen M, Martin B. Th17 T cells: linking innate and adaptive immunity. Semin Immunol 2007;19:353-361.
17. Harrington LE, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6:1123-1132.
18. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-189.
19. Bettelli E, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-238.
20. Mangan PR, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441:231-234.
21. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. The N Engl J Med 2009;361:888-898.
22. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011;29:621-663.
23. Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 2009;10:385-393.
24. Hsu HC, et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008;9:166-175.
25. 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.
26. Nakayamada S, et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 2011;35:919-931.
27. Stassen M, Schmitt E, Bopp T. From interleukin-9 to T helper 9 cells. Ann NY Acad Sci 2012;1247:56-68.
28. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 2009;10:857-863.
29. Wilhelm C, Turner JE, Van Snick J, Stockinger B. The many lives of IL-9: a question of survival? Nat Immunol 2012;13:637-641.
30. Zenewicz LA, Flavell RA. Recent advances in IL-22 biology. Int Immunol 2011;23:159-163.
31. Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002;2:389-400.
32. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775-787.
33. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531-564.
34. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009;30:616-625.
35. Tordjman R, et al. A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat Immunol 2002;3:477-482.
36. Yadav M, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 2012;209:1713-1722.
37. Weiss JM, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 2012;209:1723-1742.
38. Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory T cells (Tr1) in autoimmunity. Semin Immunol 2011;23:202-208.
39. O'Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010;327:1098-1102.
40. Yamane H, Paul WE. Memory CD4+ T cells: fate determination, positive feedback and plasticity. Cell Mol Life Sci 2012;69:1577-1583.
41. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008;112:1557-1569.
42. Shi G, Cox CA, Vistica BP, Tan C, Wawrousek EF, Gery I. Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J Immunol 2008;181:7205-7213.
43. Muranski P, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008;112:362-373.
44. Bending D, et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 2009;119:565-572.
45. Lee YK, et al. Late developmental plasticity in the T helper 17 lineage. Immunity 2009;30:92-107.
46. Hirota K, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 2011;12:255-263.
47. Lu KT, et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 2011;35:622-632.
48. King IL, Mohrs M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med 2009;206:1001-1007.
49. Zaretsky AG, Taylor JJ, King IL, Marshall FA, Mohrs M, Pearce EJ. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 2009;206:991-999.
50. Deenick EK, et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 2010;33:241-253.
51. Goenka R, et al. Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J Immunol 2011;187:1091-1095.
52. Hegazy AN, et al. Interferons direct Th2 cell reprogramming to generate a stable GATA-3+T-bet+ cell Ssubset with combined Th2 and Th1 cell functions. Immunity 2010;32:116-128.
53. Bailey-Bucktrout SL, Bluestone JA. Regulatory T cells: stability revisited. Trends Immunol 2011;32:301-306.
54. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009;106:1903-1908.
55. Tsuji M, et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009;323:1488-1492.
56. Wei G, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009;30:155-167.
57. Oldenhove G, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009;31:772-786.
58. Feng T, Cao AT, Weaver CT, Elson CO, Cong Y. Interleukin-12 converts Foxp3+ regulatory T cells to interferon-gamma-producing Foxp3+ T cells that inhibit colitis. Gastroenterology 2011;140:2031-2043.
59. Rubtsov YP, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329:1667-1671.
60. Miyao T, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012;36:262-275.
61. Hosken NA, Shibuya K, Heath AW, Murphy KM, O'Garra A. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med 1995;182:1579-1584.
62. Burstein HJ, Abbas AK. In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen. J Exp Med 1993;177:457-463.
63. Yamane H, Zhu J, Paul WE. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. J Exp Med 2005;202:793-804.
64. Iezzi G, Sonderegger I, Ampenberger F, Schmitz N, Marsland BJ, Kopf M. CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells. Proc Natl Acad Sci USA 2009;106:876-881.
65. Fazilleau N, McHeyzer-Williams LJ, Rosen H, McHeyzer-Williams MG. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol 2009;10:375-384.
66. Itoh M, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999;162:5317-5326.
67. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 2008;205:565-574.
68. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 2005;6:1219-1227.
69. Sauer S, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008;105:7797-7802.
70. Gottschalk RA, Corse E, Allison JP. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J Exp Med 2010;207:1701-1711.
71. O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012;36:542-550.
72. O'Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 2011;11:239-250.
73. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998;16:293-322.
74. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010;28:445-489.
75. Shi M, Lin TH, Appell KC, Berg LJ. Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 2008;28:763-773.
76. van Panhuys N, et al. In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation. Proc Natl Acad Sci U S A 2008;105:12423-12428.
77. Ben-Sasson SZ, Le Gros G, Conrad DH, Finkelman FD, Paul WE. IL-4 production by T cells from naive donors. IL-2 is required for IL-4 production. J Immunol 1990;145:1127-1136.
78. Cote-Sierra J, et al. Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci U S A 2004;101:3880-3885.
79. Kagami S, et al. Stat5a regulates T helper cell differentiation by several distinct mechanisms. Blood 2001;97:2358-2365.
80. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity 2003;19:739-748.
81. Liao W, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol 2008;9:1288-1296.
82. Diehl S, et al. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 2000;13:805-815.
83. Diehl S, Rincon M. The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 2002;39:531-536.
84. Stritesky GL, et al. The Transcription Factor STAT3 Is Required for T Helper 2 Cell Development. Immunity 2011;34:39-49.
85. Chen Z, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A 2006;103:8137-8142.
86. Yang XO, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007;282:9358-9363.
87. Nishihara M, et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol 2007;19:695-702.
88. Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA 2007;104:12099-12104.
89. Harris TJ, et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol 2007;179:4313-4437.
90. Ma CS, et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 2008;205:1551-1557.
91. Milner JD, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452:773-776.
92. Peters A, Lee Y, Kuchroo VK. The many faces of Th17 cells. Curr Opin Immunol 2011;23:702-706.
93. Nurieva RI, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008;29:138-149.
94. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 2008;29:127-137.
95. Poholek AC, et al. In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol 2010;185:313-326.
96. Eto D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS ONE 2011;6:e17739.
97. Zotos D, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med 2010;207:365-378.
98. Linterman MA, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med 2010;207:353-363.
99. Karnowski A, et al. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J Exp Med 2012;209:2049-2064.
100. Ma CS, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 2012;119:3997-4008.
101. Ma CS, et al. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol Cell Biol 2009;87:590-600.
102. Schmitt N, et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 2009;31:158-169.
103. Laurence A, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007;26:371-381.
104. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med 2012;209:243-250.
105. Nurieva RI, et al. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem 2012;287:11234-11239.
106. Ballesteros-Tato A, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 2012;36:847-856.
107. Yao Z, et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007;109:4368-4375.
108. Laurence A, et al. STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 2012;37:209-222.
109. Stumhofer JS, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 2006;7:937-945.
110. Hirahara K, et al. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 2012;36:1017-1030.
111. Liu L, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011;208:1635-1648.
112. Wei L, et al. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 2010;32:840-851.
113. Yang XP, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 2011;12:247-254.
114. Cho JY, Grigura V, Murphy TL, Murphy K. Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-gamma promoter. Int Immunol 2003;15:1149-1160.
115. Sekimata M, et al. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus. Immunity 2009;31:551-564.
116. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997;89:587-596.
117. Ivanov II, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006;126:1121-1133.
118. Chang HC, et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 2010;11:527-534.
119. Johnston RJ, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009;325:1006-1010.
120. Nurieva RI, et al. Bcl6 mediates the development of T follicular helper cells. Science 2009;325:1001-1005.
121. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
122. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
123. Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005;307:430-433.
124. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009;10:595-602.
125. Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 2011;35:337-348.
126. Chung Y, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 2011;17:983-988.
127. Wohlfert EA, et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 2011;121:4503-4515.
128. Linterman MA, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 2011;17:975-982.
129. Koch MA, Thomas KR, Perdue NR, Smigiel KS, Srivastava S, Campbell DJ. T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 2012;37:501-510.
130. Hall AO, et al. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 2012;37:511-523.
131. Chaudhry A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009;326:986-991.
132. Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, Jenkins MK. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 2011;35:583-595.
133. Oestreich KJ, Huang AC, Weinmann AS. The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J Exp Med 2011;208:1001-1013.
134. Oestreich KJ, Mohn SE, Weinmann AS. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol 2012;13:405-411.
135. Zhang JA, Mortazavi A, Williams BA, Wold BJ, Rothenberg EV. Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity. Cell 2012;149:467-482.
136. Xiong Y, Bosselut R. CD4-CD8 differentiation in the thymus: connecting circuits and building memories. Curr Opin Immunol 2012;24:139-145.
137. Zheng Y, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009;458:351-356.
138. Ahyi AN, Chang HC, Dent AL, Nutt SL, Kaplan MH. IFN regulatory factor 4 regulates the expression of a subset of Th2 cytokines. J Immunol 2009;183:1598-1606.
139. Staudt V, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 2010;33:192-202.
140. Brustle A, et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 2007;8:958-966.
141. Kwon H, et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 2009;31:941-952.
142. Glasmacher E, et al. A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 2012;338:975-980.
143. Li P, et al. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 2012;490:543-546.
144. Ciofani M, et al. A validated regulatory network for th17 cell specification. Cell 2012;151:289-303.
145. Ho IC, Hodge MR, Rooney JW, Glimcher LH. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 1996;85:973-983.
146. Bauquet AT, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 2009;10:167-175.
147. Mullen AC, et al. Hlx is induced by and genetically interacts with T-bet to promote heritable THI gene induction. Nat Immunol 2002;3:652-658.
148. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol 2007;8:145-153.
149. Grenningloh R, Kang BY, Ho IC. Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses. J Exp Med 2005;201:615-626.
150. Li B, Tournier C, Davis RJ, Flavell RA. Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 1999;18:420-432.
151. Zhu J, et al. Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. Immunity 2002;16:733-744.
152. Dang EV, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011;146:772-784.
153. Lazarevic V, et al. T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORgammat. Nat Immunol 2011;12:96-104.
154. Quintana FJ, et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat Immunol 2012;13:770-777.
155. Hamalainen H, Zhou H, Chou W, Hashizume H, Heller R, Lahesmaa R. Distinct gene expression profiles of human type 1 and type 2 T helper cells. Genome Biol 2001;2:1-11. RESEARCH0022.
156. Rogge L, et al. Transcript imaging of the development of human T helper cells using oligonucleotide arrays. Nat Genet 2000;25:96-101.
157. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008;5:621-628.
158. Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med 2008;205:1993-2004.
159. Zhou X, et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med 2008;205:1983-1991.
160. Koralov SB, et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 2008;132:860-874.
161. Kuchen S, et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 2010;32:828-839.
162. Rossi RL, et al. Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. Nat Immunol 2011;12:796-803.
163. Stittrich AB, et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol 2010;11:1057-1062.
164. Takahashi H, et al. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol 2012;13:587-595.
165. Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem 2012;81:145-166.
166. Barlow DP, Stoger R, Herrmann BG, Saito K, Schweifer N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 1991;349:84-87.
167. Brown CJ, et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 1991;349:38-44.
168. Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM. Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol 2012;189:2084-2088.
169. ENCODE. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57-74.
170. Amsen D, Spilianakis CG, Flavell RA. How are T(H)1 and T(H)2 effector cells made? Curr Opin Immunol 2009;21:153-160.
171. Aune TM, Collins PL, Chang S. Epigenetics and T helper 1 differentiation. Immunology 2009;126:299-305.
172. Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 2009;9:91-105.
173. Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol 2003;4:616-623.
174. Kanno Y, Vahedi G, Hirahara K, Singleton K, O'Shea JJ. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 2012;30:707-731.
175. Oestreich KJ, Weinmann AS. Encoding stability versus flexibility: lessons learned from examining epigenetics in T helper cell differentiation. Curr Top Microbiol Immunol 2012;356:145-164.
176. Zhang F, Boothby M. T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent. J Exp Med 2006;203:1493-1505.
177. Kagey MH, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 2010;467:430-435.
178. Hadjur S, et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 2009;460:410-413.
179. Yamashita M, et al. Crucial role of MLL for the maintenance of memory T helper type 2 cell responses. Immunity 2006;24:611-622.
180. Onodera A, et al. STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells. J Exp Med 2010;207:2493-2506.
181. Allan RS, et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 2012;487:249-253.
182. 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.
183. Floess S, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5:e38.
184. Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009;9:83-89.
185. Xu L, Kitani A, Stuelten C, McGrady G, Fuss I, Strober W. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 2010;33:313-325.
186. Park PJ. ChIP-seq: advantages and challenges of a maturing technology. Nat Rev Genet 2009;10:669-680.
187. Wang YH, et al. A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med 2010;207:2479-2491.
188. Durant L, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 2010;32:605-615.
189. Hoey T, et al. Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses. EMBO J 2003;22:4237-4248.
190. Lund RJ, Chen Z, Scheinin J, Lahesmaa R. Early target genes of IL-12 and STAT4 signaling in th cells. J Immunol 2004;172:6775-6782.
191. Elo LL, et al. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity 2010;32:852-862.
192. Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007;445:936-940.
193. Ivanov II, Zhou L, Littman DR. Transcriptional regulation of Th17 cell differentiation. Semin Immunol 2007;19:409-417.
194. Ramana CV, Chatterjee-Kishore M, Nguyen H, Stark GR. Complex roles of Stat1 in regulating gene expression. Oncogene 2000;19:2619-2627.
195. Korn T, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448:484-487.
196. Yang XO, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008;28:29-39.
197. Miller SA, Weinmann AS. Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunol Rev 2010;238:233-246.
198. Beima KM, Miazgowicz MM, Lewis MD, Yan PS, Huang TH, Weinmann AS. T-bet binding to newly identified target gene promoters is cell type-independent but results in variable context-dependent functional effects. J Biol Chem 2006;281:11992-12000.
199. Nguyen KB, et al. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 2002;297:2063-2066.
200. Kao C, et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 2011;12:663-671.
201. Zhu J, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity 2012;37:660-673.
202. Wei G, et al. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 2011;35:299-311.
203. Samstein RM, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012;151:153-166.
204. Gavin MA, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007;445:771-775.
205. Rudra D, et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 2012;13:1010-1019.
206. McMurchy AN, et al. A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood 2012;doi:10.1182/blood-2012-05-431023.
207. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011;241:260-268.
208. Basso K, Dalla-Favera R. BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol 2010;105:193-210.
209. Arima M, et al. A putative silencer element in the IL-5 gene recognized by Bcl6. J Immunol 2002;169:829-836.
210. Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 2010;11:114-120.
211. Yu D, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009;31:457-468.
212. Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 2006;24:607-656.
213. Harada Y, et al. The 3' enhancer CNS2 Is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells. Immunity 2012;36:188-200.
214. Spilianakis CG, Flavell RA. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat Immunol 2004;5:1017-1027.
215. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 2012;150:29-38.
216. Vahedi G, et al. STATs shape the active enhancer landscape of T cell populations. Cell 2012;151:981-993.
217. Mercer E, et al. Multilineage priming of enhancer repertoires precedes commitment to the B and myeloid cell lineages in hematopoietic progenitors. Immunity 2011;35:413-425.
218. Biddie S, et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 2011;43:145-155.