Abstract
CD4+ helper T cells are crucial for autoimmune and infectious diseases; however, the recognition of the many, diverse fates available continues unabated. Precisely what controls specification of helper T cells and preserves phenotypic commitment is currently intensively investigated. In this review, we will discuss the major factors that impact helper T cell fate choice, ranging from cytokines and the microbiome to metabolic control and epigenetic regulation. We will also discuss the technological advances along with the attendant challenges presented by “big data,” which allow the understanding of these processes on comprehensive scales.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abarrategui I, Krangel MS (2006) Regulation of T cell receptor-alpha gene recombination by transcription. Nat Immunol 7(10):1109–1115. doi:10.1038/ni1379
Abarrategui I, Krangel MS (2007) Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. EMBO J 26(20):4380–4390. doi:10.1038/sj.emboj.7601866
Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14(4):307–308. doi:10.1038/ni.2554
Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383(6603):787–793
Absher DM, Li X, Waite LL, Gibson A, Roberts K, Edberg J, Chatham WW, Kimberly RP (2013) Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS Genet 9(8):e1003678. doi:10.1371/journal.pgen.1003678
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007a) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8(9):942–949
Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007b) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8(6):639–646
Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, Powrie F (2010) Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33(2):279–288. doi:10.1016/j.immuni.2010.08.010
Ahyi AN, Chang HC, Dent AL, Nutt SL, Kaplan MH (2009) IFN regulatory factor 4 regulates the expression of a subset of Th2 cytokines. J Immunol 183(3):1598–1606. doi:10.4049/jimmunol.0803302
Altorok N, Coit P, Hughes T, Koelsch KA, Stone DU, Rasmussen A, Radfar L, Scofield RH, Sivils KL, Farris AD, Sawalha AH (2013) Genome-wide DNA methylation patterns in naive CD4 T cells from patients with primary Sjogren’s syndrome. Arthritis Rheum. doi:10.1002/art.38264
Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C (2009) The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31(2):220–231. doi:10.1016/j.immuni.2009.06.024
Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204(8):1849–1861
Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607–656. doi:10.1146/annurev.immunol.23.021704.115821
Ansel KM, Lee DU, Rao A (2003) An epigenetic view of helper T cell differentiation. Nat Immunol 4(7):616–623
Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455. doi:10.1038/nature12726
Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500(7461):232–236. doi:10.1038/nature12331
Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341. doi:10.1126/science.1198469
Aune TM, Collins PL, Collier SP, Henderson MA, Chang S (2013) Epigenetic activation and silencing of the gene that encodes IFN-γ. Front Immunol 4:112. doi:10.3389/fimmu.2013.00112
Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8(12):1380–1389. doi:10.1038/ni1541
Bailey-Bucktrout SL, Bluestone JA (2011) Regulatory T cells: stability revisited. Trends Immunol 32(7):301–306. doi:10.1016/j.it.2011.04.002
Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39 (5):949–962. doi:10.1016/j.immuni.2013.10.016
Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36(5):847–856. doi:10.1016/j.immuni.2012.02.012
Bandukwala HS, Gagnon J, Togher S, Greenbaum JA, Lamperti ED, Parr NJ, Molesworth AM, Smithers N, Lee K, Witherington J, Tough DF, Prinjha RK, Peters B, Rao A (2012) Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci USA 109(36):14532–14537. doi:10.1073/pnas.1212264109
Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155 inhibits IFN-gamma signaling in CD4+ T cells. Eur J Immunol 40(1):225–231. doi:10.1002/eji.200939381
Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, Thiel A, Boeld TJ, Hoffmann P, Edinger M, Turbachova I, Hamann A, Olek S, Huehn J (2007) DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 37(9):2378–2389
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. doi:10.1016/j.cell.2009.01.002
Battaglia M, Gregori S, Bacchetta R, Roncarolo MG (2006) Tr1 cells: from discovery to their clinical application. Semin Immunol 18(2):120–127. doi:10.1016/j.smim.2006.01.007
Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7(9):929–936
Bauer H, Horowitz RE, Levenson SM, Popper H (1963) The response of the lymphatic tissue to the microbial flora. Studies on germfree mice. Am J Pathol 42:471–483
Baumjohann D, Ansel KM (2013) MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 13(9):666–678. doi:10.1038/nri3494
Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M, Ansel KM, Jeker LT (2013) The microRNA cluster miR-17 approximately 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol 14(8):840–848. doi:10.1038/ni.2642
Beck JM, Young VB, Huffnagle GB (2012) The microbiome of the lung. Transl Res 160(4):258–266. doi:10.1016/j.trsl.2012.02.005
Bending D, De La Pena H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, Cooke A (2009) Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Investig
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21. doi:10.1038/83713
Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, Hafler DA (2009) IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113(18):4240–4249
Bernstein E, Allis CD (2005) RNA meets chromatin. Genes Develop 19(14):1635–1655. doi:10.1101/gad.1324305
Bestor T, Laudano A, Mattaliano R, Ingram V (1988) Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol 203(4):971–983
Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermuller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaoz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Loytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Xu M, Haidar JN, Yu Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrimsdottir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ (2007) Identification and analysis of functional elements in 1 % of the human genome by the ENCODE pilot project. Nature 447(7146):799–816. doi:10.1038/nature05874
Biswas PS, Gupta S, Chang E, Song L, Stirzaker RA, Liao JK, Bhagat G, Pernis AB (2010) Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Investig 120(9):3280–3295. doi:10.1172/JCI42856
Bluml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, Hayer S, Koenders MI, van den Berg WB, Smolen J, Redlich K (2011) Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum 63(5):1281–1288. doi:10.1002/art.30281
Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, Garcia-Flores Y, Luong M, Devrekanli A, Xu J, Sun G, Tay J, Linsley PS, Baltimore D (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208(6):1189–1201. doi:10.1084/jem.20101823
Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, Pierce R, McClanahan TK, Sadekova S, Malefyt RD (2010) Human Th17 Cells Comprise Heterogeneous Subsets including IFN-γ-Producing Cells with Distinct Properties from the Th1 Lineage. J Immunol
Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA (1997) Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7(5):679–689
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27(1):68–73. doi:10.1038/83784
Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8(9):958–966. doi:10.1038/ni1500
Burzyn D, Benoist C, Mathis D (2013a) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14(10):1007–1013. doi:10.1038/ni.2683
Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C, Mathis D (2013b) A special population of regulatory T cells potentiates muscle repair. Cell 155(6):1282–1295. doi:10.1016/j.cell.2013.10.054
Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25(18):1915–1927. doi:10.1101/gad.17446611
Cai S, Lee CC, Kohwi-Shigematsu T (2006) SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet 38(11):1278–1288. doi:10.1038/ng1913
Cannons JL, Lu KT, Schwartzberg PL (2013) T follicular helper cell diversity and plasticity. Trends Immunol 34(5):200–207. doi:10.1016/j.it.2013.01.001
Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y (2005) The transcriptional landscape of the mammalian genome. Science 309(5740):1559–1563. doi:10.1126/science.1112014
Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY (2009) CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326(5955):986–991. doi:10.1126/science.1172702
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+ CD25- naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886. doi:10.1084/jem.20030152
Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park BV, Pan Z, Dang E, Wang H, Luo W, Li L, Semenza GL, Zheng SG, Loser K, Tsun A, Greene MI, Pardoll DM, Pan F, Li B (2013) The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39(2):272–285. doi:10.1016/j.immuni.2013.08.006
Chen Z, Tato CM, Muul L, Laurence A, O’Shea JJ (2007) Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 56(9):2936–2946
Choi J, Jang H, Kim H, Lee JH, Kim ST, Cho EJ, Youn HD (2014) Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation. Nucleic Acids Res 42(1):224–234. doi:10.1093/nar/gkt873
Chong MM, Rasmussen JP, Rudensky AY, Littman DR (2008) The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med 205(9):2005–2017. doi:10.1084/jem.20081219
Christie GR, Hajduch E, Hundal HS, Proud CG, Taylor PM (2002) Intracellular sensing of amino acids in Xenopus laevis oocytes stimulates p70 S6 kinase in a target of rapamycin-dependent manner. J Biol Chem 277(12):9952–9957. doi:10.1074/jbc.M107694200
Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17(8):983–988. doi:10.1038/nm.2426
Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486(7404):549–553. doi:10.1038/nature11132
Coccia EM, Cicala C, Charlesworth A, Ciccarelli C, Rossi GB, Philipson L, Sorrentino V (1992) Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol 12(8):3514–3521
Cohen CJ, Crome SQ, MacDonald KG, Dai EL, Mager DL, Levings MK (2011) Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol 187(11):5615–5626. doi:10.4049/jimmunol.1101058
Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM (2012) Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol 189(5):2084–2088. doi:10.4049/jimmunol.1200774
Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK (2011) Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm Med 11:29. doi:10.1186/1471-2466-11-29
Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569. doi:10.1038/nature06306
Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204(8):1757–1764. doi:10.1084/jem.20070590
Coomes SM, Pelly VS, Wilson MS (2013) Plasticity within the alphabeta(+)CD4(+) T-cell lineage: when, how and what for? Open Biol 3(1):120157. doi:10.1098/rsob.120157
Corcoran AE (2010) The epigenetic role of non-coding RNA transcription and nuclear organization in immunoglobulin repertoire generation. Semin Immunol 22(6):353–361. doi:10.1016/j.smim.2010.08.001
Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B (1988) Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol 140(7):2197–2200
Corvetta A, Della Bitta R, Luchetti MM, Pomponio G (1991) 5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases. J Chromatogr 566(2):481–491
Cosmi L, Cimaz R, Maggi L, Santarlasci V, Capone M, Borriello F, Frosali F, Querci V, Simonini G, Barra G, Piccinni MP, Liotta F, De Palma R, Maggi E, Romagnani S, Annunziato F (2011) Evidence of the transient nature of the Th17 phenotype of CD4+ CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis. Arthritis Rheum 63(8):2504–2515. doi:10.1002/art.30332
Crome SQ, Lang PA, Lang KS, Ohashi PS (2013) Natural killer cells regulate diverse T cell responses. Trends Immunol 34(7):342–349. doi:10.1016/j.it.2013.03.002
Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29:621–663. doi:10.1146/annurev-immunol-031210-101400
Crotty S (2012) The 1-1-1 fallacy. Immunol Rev 247(1):133–142. doi:10.1111/j.1600-065X.2012.01117.x
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. doi:10.1016/j.cell.2011.07.033
Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 9(12):1347–1355. doi:10.1038/ni.1677
de Wit E, Bouwman BA, Zhu Y, Klous P, Splinter E, Verstegen MJ, Krijger PH, Festuccia N, Nora EP, Welling M, Heard E, Geijsen N, Poot RA, Chambers I, de Laat W (2013) The pluripotent genome in three dimensions is shaped around pluripotency factors. Nature 501(7466):227–231. doi:10.1038/nature12420
Deenick EK, Chan A, Ma CS, Gatto D, Schwartzberg PL, Brink R, Tangye SG (2010) Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33(2):241–253. doi:10.1016/j.immuni.2010.07.015
Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30(6):832–844. doi:10.1016/j.immuni.2009.04.014
Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12(4):295–303. doi:10.1038/ni.2005
Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256. doi:10.1038/nature12428
Denholtz M, Bonora G, Chronis C, Splinter E, de Laat W, Ernst J, Pellegrini M, Plath K (2013) Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. Cell Stem Cell 13(5):602–616. doi:10.1016/j.stem.2013.08.013
Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22(9):1775–1789. doi:10.1101/gr.132159.111
Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398):376–380. doi:10.1038/nature11082
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, Roder 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, Guigo R, Gingeras TR (2012) Landscape of transcription in human cells. Nature 489(7414):101–108. doi:10.1038/nature11233
Dong C (2011) Genetic controls of Th17 cell differentiation and plasticity. Exp Mol Med 43(1):1–6. doi:10.3858/emm.2011.43.1.007
Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10(8):857–863. doi:10.1038/ni.1767
Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, Shteyer E, Filiz S, Chee R, Elawad M, Hartmann B, Arkwright PD, Dvorak C, Klein C, Puck JM, Grimbacher B, Glocker EO (2013) Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 131(3):825–830. doi:10.1016/j.jaci.2012.09.025
Escobar T, Yu CR, Muljo SA, Egwuagu CE (2013) STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 54(6):4017–4025. doi:10.1167/iovs.13-11937
Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, Yusuf I, Crotty S (2011) 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 6(3):e17739. doi:10.1371/journal.pone.0017739
Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–379. doi:10.1146/annurev-biochem-060308-103103
Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5(2):e38
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4(4):330–336. doi:10.1038/ni904
Fox CJ, Hammerman PS, Thompson CB (2005) Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 5(11):844–852. doi:10.1038/nri1710
Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS, Gazit R, Adoro S, Glimcher L, Chan S, Kastner P, Rossi D, Collins JJ, Mathis D, Benoist C (2012) A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells. Nat Immunol 13(10):972–980. doi:10.1038/ni.2420
Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450. doi:10.1038/nature12721
Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, Eberl G, Snel J, Kelly D, Cerf-Bensussan N (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31(4):677–689. doi:10.1016/j.immuni.2009.08.020
Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739–746. doi:10.1038/nm.3179
Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416(3):375–385. doi:10.1042/BJ20081668
Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, McCoy KD, Macpherson AJ (2011) Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34(5):794–806. doi:10.1016/j.immuni.2011.03.021
Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E, Gregory L, Lonie L, Chew A, Wei CL, Ragoussis J, Natoli G (2010) Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32(3):317–328. doi:10.1016/j.immuni.2010.02.008
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467 (7318):967–971
Gibcus JH, Dekker J (2013) The hierarchy of the 3D genome. Mol Cell 49(5):773–782. doi:10.1016/j.molcel.2013.02.011
Glatman Zaretsky A, Taylor JJ, King IL, Marshall FA, Mohrs M, Pearce EJ (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206(5):991–999. doi:10.1084/jem.20090303
Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361(21):2033–2045. doi:10.1056/NEJMoa0907206
Goenka R, Barnett LG, Silver JS, O’Neill PJ, Hunter CA, Cancro MP, Laufer TM (2011) Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J Immunol 187(3):1091–1095. doi:10.4049/jimmunol.1100853
Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514. doi:10.1146/annurev.biochem.74.010904.153721
Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard K (2013) The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152(4):743–754. doi:10.1016/j.cell.2013.01.015
Gordan JD, Thompson CB, Simon MC (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12(2):108–113. doi:10.1016/j.ccr.2007.07.006
Gregori S, Goudy KS, Roncarolo MG (2012) The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front Immunol 3:30. doi:10.3389/fimmu.2012.00030
Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC, Bouffard GG, Blakesley RW, Murray PR, Green ED, Turner ML, Segre JA (2009) Topographical and temporal diversity of the human skin microbiome. Science 324(5931):1190–1192. doi:10.1126/science.1171700
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871. doi:10.1016/j.devcel.2006.10.007
Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458(7235):223–227. doi:10.1038/nature07672
Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang X, Amit I, Meissner A, Regev A, Rinn JL, Root DE, Lander ES (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477(7364):295–300. doi:10.1038/nature10398
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30(2):214–226. doi:10.1016/j.molcel.2008.03.003
Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, Merkenschlager M (2009) Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460(7253):410–413. doi:10.1038/nature08079
Hall JA, Bouladoux N, Sun CM, Wohlfert EA, Blank RB, Zhu Q, Grigg ME, Berzofsky JA, Belkaid Y (2008) Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29(4):637–649. doi:10.1016/j.immuni.2008.08.009
Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagan AJ, Pepper M, Maynard CL, Elson CO 3rd, Belkaid Y (2012) Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337(6101):1553–1556. doi:10.1126/science.1220961
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388. doi:10.1038/nature11993
Hansen W, Hutzler M, Abel S, Alter C, Stockmann C, Kliche S, Albert J, Sparwasser T, Sakaguchi S, Westendorf AM, Schadendorf D, Buer J, Helfrich I (2012) Neuropilin 1 deficiency on CD4+ Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med 209(11):2001–2016. doi:10.1084/jem.20111497
Harada Y, Tanaka S, Motomura Y, Ohno S, Yanagi Y, Inoue H, Kubo M (2012) The 3′ enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells. Immunity 36(2):188–200. doi:10.1016/j.immuni.2012.02.002
Harker JA, Lewis GM, Mack L, Zuniga EI (2011) Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334(6057):825–829. doi:10.1126/science.1208421
Hegazy AN, Peine M, Helmstetter C, Panse I, Frohlich A, Bergthaler A, Flatz L, Pinschewer DD, Radbruch A, Lohning M (2010) Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity 32 (1):116–128
Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, Ye Z, Lee LK, Stuart RK, Ching CW, Ching KA, Antosiewicz-Bourget JE, Liu H, Zhang X, Green RD, Lobanenkov VV, Stewart R, Thomson JA, Crawford GE, Kellis M, Ren B (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459(7243):108–112. doi:10.1038/nature07829
Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38(4):576–589. doi:10.1016/j.molcel.2010.05.004
Hirahara K, Vahedi G, Ghoreschi K, Yang XP, Nakayamada S, Kanno Y, O’Shea JJ, Laurence A (2011) Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 134(3):235–245. doi:10.1111/j.1365-2567.2011.03483.x
Hooper LV, Macpherson AJ (2010) Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 10(3):159–169. doi:10.1038/nri2710
Hori S (2011) Regulatory T cell plasticity: beyond the controversies. Trends Immunol 32(7):295–300. doi:10.1016/j.it.2011.04.004
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. doi:10.1126/science.1079490
Horwitz DA, Zheng SG, Gray JD (2008) Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol 29(9):429–435
Hu G, Tang Q, Sharma S, Yu F, Escobar TM, Muljo SA, Zhu J, Zhao K (2013a) Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat Immunol 14(11):1190–1198. doi:10.1038/ni.2712
Hu R, Huffaker TB, Kagele DA, Runtsch MC, Bake E, Chaudhuri AA, Round JL, O’Connell RM (2013b) MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. J Immunol 190(12):5972–5980. doi:10.4049/jimmunol.1300351
Huber M, Brustle A, Reinhard K, Guralnik A, Walter G, Mahiny A, von Low E, Lohoff M (2008) IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci USA 105(52):20846–20851. doi:10.1073/pnas.0809077106
Huehn J, Polansky JK, Hamann A (2009) Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 9(2):83–89. doi:10.1038/nri2474
Huffaker TB, Hu R, Runtsch MC, Bake E, Chen X, Zhao J, Round JL, Baltimore D, O’Connell RM (2012) Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep 2(6):1697–1709. doi:10.1016/j.celrep.2012.10.025
Hwang ES, Hong JH, Glimcher LH (2005a) IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508. J Exp Med 202(9):1289–1300. doi:10.1084/jem.20051044
Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH (2005b) T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307(5708):430–433. doi:10.1126/science.1103336
Ingolia NT, Lareau LF, Weissman JS (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147(4):789–802. doi:10.1016/j.cell.2011.10.002
Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139(3):485–498. doi:10.1016/j.cell.2009.09.033
Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4(4):337–349. doi:10.1016/j.chom.2008.09.009
Jang EJ, Park HR, Hong JH, Hwang ES (2013) Lysine 313 of T-box is crucial for modulation of protein stability, DNA binding, and threonine phosphorylation of T-bet. J Immunol 190(11):5764–5770. doi:10.4049/jimmunol.1203403
Janson PC, Winerdal ME, Marits P, Thorn M, Ohlsson R, Winqvist O (2008) FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS ONE 3(2):e1612
Jin F, Li Y, Dixon JR, Selvaraj S, Ye Z, Lee AY, Yen CA, Schmitt AD, Espinoza CA, Ren B (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503(7475):290–294. doi:10.1038/nature12644
Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S (2012) STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med 209(2):243–250. doi:10.1084/jem.20111174
Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325(5943):1006–1010. doi:10.1126/science.1175870
Joosten LA, Leoni F, Meghji S, Mascagni P (2011) Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol Med 17(5–6):391–396. doi:10.2119/molmed.2011.00058
Junker A (2011) Pathophysiology of translational regulation by microRNAs in multiple sclerosis. FEBS Lett 585(23):3738–3746. doi:10.1016/j.febslet.2011.03.052
Kane LP, Andres PG, Howland KC, Abbas AK, Weiss A (2001) Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Nat Immunol 2(1):37–44. doi:10.1038/83144
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. doi:10.1146/annurev-immunol-020711-075058
Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484–1488. doi:10.1126/science.1138341
Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA 106(28):11667–11672. doi:10.1073/pnas.0904715106
Kieffer-Kwon KR, Tang Z, Mathe E, Qian J, Sung MH, Li G, Resch W, Baek S, Pruett N, Grontved L, Vian L, Nelson S, Zare H, Hakim O, Reyon D, Yamane A, Nakahashi H, Kovalchuk AL, Zou J, Joung JK, Sartorelli V, Wei CL, Ruan X, Hager GL, Ruan Y, Casellas R (2013) Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell 155(7):1507–1520. doi:10.1016/j.cell.2013.11.039
Kim JS, Sklarz T, Banks LB, Gohil M, Waickman AT, Skuli N, Krock BL, Luo CT, Hu W, Pollizzi KN, Li MO, Rathmell JC, Birnbaum MJ, Powell JD, Jordan MS, Koretzky GA (2013) Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat Immunol 14(6):611–618. doi:10.1038/ni.2607
Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465(7295):182–187. doi:10.1038/nature09033
King IL, Mohrs M (2009) IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med 206(5):1001–1007. doi:10.1084/jem.20090313
Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP (2010) Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 3 (107):ra8. doi:10.1126/scisignal.2000568
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496(7446):518–522. doi:10.1038/nature11868
Koch MA, Thomas KR, Perdue NR, Smigiel KS, Srivastava S, Campbell DJ (2012) T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 37(3):501–510. doi:10.1016/j.immuni.2012.05.031
Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10(6):595–602
Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-Hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H (2014) Pathogenic conversion of Foxp3(+) T cells into TH17 cells in autoimmune arthritis. Nat Med 20(1):62–68. doi:10.1038/nm.3432
Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448(7152):484–487
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517. doi:10.1146/annurev.immunol.021908.132710
Kurowska-Stolarska M, Alivernini S, Ballantine LE, Asquith DL, Millar NL, Gilchrist DS, Reilly J, Ierna M, Fraser AR, Stolarski B, McSharry C, Hueber AJ, Baxter D, Hunter J, Gay S, Liew FY, McInnes IB (2011) MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci USA 108(27):11193–11198. doi:10.1073/pnas.1019536108
Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim HP, Oh J, Tunyaplin C, Carotta S, Donovan CE, Goldman ML, Tailor P, Ozato K, Levy DE, Nutt SL, Calame K, Leonard WJ (2009) Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31(6):941–952. doi:10.1016/j.immuni.2009.10.008
Lafont V, Astoul E, Laurence A, Liautard J, Cantrell D (2000) The T cell antigen receptor activates phosphatidylinositol 3-kinase-regulated serine kinases protein kinase B and ribosomal S6 kinase 1. FEBS Lett 486(1):38–42
Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS (2009) Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 182(1):259–273
Laurence A, Amarnath S, Mariotti J, Kim YC, Foley J, Eckhaus M, O’Shea JJ, Fowler DH (2012) STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37(2):209–222. doi:10.1016/j.immuni.2012.05.027
Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, Perez-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
Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13(10):991–999. doi:10.1038/ni.2416
Lee YK, Mukasa R, Hatton RD, Weaver CT (2009) Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol 21(3):274–280
Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, Modena D, Moras ML, Pozzi P, Reznikov LL, Siegmund B, Fantuzzi G, Dinarello CA, Mascagni P (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 11(1–12):1–15. doi:10.2119/2006-00005.Dinarello
Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, Dona G, Fossati G, Sozzani S, Azam T, Bufler P, Fantuzzi G, Goncharov I, Kim SH, Pomerantz BJ, Reznikov LL, Siegmund B, Dinarello CA, Mascagni P (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 99(5):2995–3000. doi:10.1073/pnas.052702999
Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124(4):837–848. doi:10.1016/j.cell.2006.02.017
Li G, Yu M, Lee WW, Tsang M, Krishnan E, Weyand CM, Goronzy JJ (2012) Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med 18(10):1518–1524. doi:10.1038/nm.2963
Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134(3):392–404. doi:10.1016/j.cell.2008.07.025
Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25(3):455–471. doi:10.1016/j.immuni.2006.07.011
Li MO, Wan YY, Flavell RA (2007a) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26(5):579–591. doi:10.1016/j.immuni.2007.03.014
Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, Liu G, Braich R, Manoharan M, Soutschek J, Skare P, Klein LO, Davis MM, Chen CZ (2007b) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129(1):147–161. doi:10.1016/j.cell.2007.03.008
Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, Oh S, Kim HS, Glass CK, Rosenfeld MG (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498(7455):516–520. doi:10.1038/nature12210
Liao W, Lin JX, Wang L, Li P, Leonard WJ (2011) Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol 12(6):551–559. doi:10.1038/ni.2030
Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, Sandstrom R, Bernstein B, Bender MA, Groudine M, Gnirke A, Stamatoyannopoulos J, Mirny LA, Lander ES, Dekker J (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293. doi:10.1126/science.1181369
Lin HS, Hu CY, Chan HY, Liew YY, Huang HP, Lepescheux L, Bastianelli E, Baron R, Rawadi G, Clement-Lacroix P (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150(7):862–872. doi:10.1038/sj.bjp.0707165
Liston A, Lu LF, O’Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med 205(9):1993–2004. doi:10.1084/jem.20081062
Lochner M, Peduto L, Cherrier M, Sawa S, Langa F, Varona R, Riethmacher D, Si-Tahar M, Di Santo JP, Eberl G (2008) In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 205(6):1381–1393
Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, Garber M, Curran M, Onder T, Agarwal S, Manos PD, Datta S, Lander ES, Schlaeger TM, Daley GQ, Rinn JL (2010) Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 42(12):1113–1117. doi:10.1038/ng.710
Lohoff M, Mittrucker HW, Prechtl S, Bischof S, Sommer F, Kock S, Ferrick DA, Duncan GS, Gessner A, Mak TW (2002) Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci USA 99(18):11808–11812. doi:10.1073/pnas.182425099
Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-β. J Biol Chem 285(53):41328–41336. doi:10.1074/jbc.M110.146852
Lu KT, Kanno Y, Cannons JL, Handon R, Bible P, Elkahloun AG, Anderson SM, Wei L, Sun H, O’Shea JJ, Schwartzberg PL (2011) Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 35(4):622–632. doi:10.1016/j.immuni.2011.07.015
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142(6):914–929. doi:10.1016/j.cell.2010.08.012
Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY (2009) Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30(1):80–91. doi:10.1016/j.immuni.2008.11.010
Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, Arkwright PD, Kreins AY, Averbuch D, Engelhard D, Magdorf K, Kilic SS, Minegishi Y, Nonoyama S, French MA, Choo S, Smart JM, Peake J, Wong M, Gray P, Cook MC, Fulcher DA, Casanova JL, Deenick EK, Tangye SG (2012) Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119(17):3997–4008. doi:10.1182/blood-2011-11-392985
Maeda N, Kasukawa T, Oyama R, Gough J, Frith M, Engstrom PG, Lenhard B, Aturaliya RN, Batalov S, Beisel KW, Bult CJ, Fletcher CF, Forrest AR, Furuno M, Hill D, Itoh M, Kanamori-Katayama M, Katayama S, Katoh M, Kawashima T, Quackenbush J, Ravasi T, Ring BZ, Shibata K, Sugiura K, Takenaka Y, Teasdale RD, Wells CA, Zhu Y, Kai C, Kawai J, Hume DA, Carninci P, Hayashizaki Y (2006) Transcript annotation in FANTOM3: mouse gene catalog based on physical cDNAs. PLoS Genet 2(4):e62. doi:10.1371/journal.pgen.0020062
Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S (2011) Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol 41(6):1652–1662. doi:10.1002/eji.201041120
Makar KW, Perez-Melgosa M, Shnyreva M, Weaver WM, Fitzpatrick DR, Wilson CB (2003) Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Nat Immunol 4(12):1183–1190. doi:10.1038/ni1004
Malik N, Rao MS (2013) A review of the methods for human iPSC derivation. Methods Mol Biol 997:23–33. doi:10.1007/978-1-62703-348-0_3
Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441(7090):231–234
Marahrens Y, Panning B, Dausman J, Strauss W, Jaenisch R (1997) Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev 11(2):156–166
Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445(7130):931–935. doi:10.1038/nature05478
Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF (2009) RNA regulation of epigenetic processes. Bioessays 31(1):51–59. doi:10.1002/bies.080099
Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122(1):107–118. doi:10.1016/j.cell.2005.05.007
McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397
McGeachy MJ, Cua DJ (2008) Th17 cell differentiation: the long and winding road. Immunity 28(4):445–453
Mele DA, Salmeron A, Ghosh S, Huang HR, Bryant BM, Lora JM (2013) BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210(11):2181–2190. doi:10.1084/jem.20130376
Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Leveille N, Kalluri R, de Laat W, Agami R (2013) eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49(3):524–535. doi:10.1016/j.molcel.2012.11.021
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495(7441):333–338. doi:10.1038/nature11928
Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36(2):262–275. doi:10.1016/j.immuni.2011.12.012
Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173
Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT (2008) Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci 121(Pt 7):939–946. doi:10.1242/jcs.024646
Mousavi K, Zare H, Dell’orso S, Grontved L, Gutierrez-Cruz G, Derfoul A, Hager GL, Sartorelli V (2013) eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci. Mol Cell 51(5):606–617. doi:10.1016/j.molcel.2013.07.022
Mucida D, Husain MM, Muroi S, van Wijk F, Shinnakasu R, Naoe Y, Reis BS, Huang Y, Lambolez F, Docherty M, Attinger A, Shui JW, Kim G, Lena CJ, Sakaguchi S, Miyamoto C, Wang P, Atarashi K, Park Y, Nakayama T, Honda K, Ellmeier W, Kronenberg M, Taniuchi I, Cheroutre H (2013) Transcriptional reprogramming of mature CD4(+) helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol 14(3):281–289. doi:10.1038/ni.2523
Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835):256–260. doi:10.1126/science.1145697
Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, Crawford GE, Hatton RD, Weaver CT (2010) Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32 (5):616–627
Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL (2011) Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol 187(5):2213–2221. doi:10.4049/jimmunol.1003952
Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, Deming C, Quinones M, Koo L, Conlan S, Spencer S, Hall JA, Dzutsev A, Kong H, Campbell DJ, Trinchieri G, Segre JA, Belkaid Y (2012) Compartmentalized control of skin immunity by resident commensals. Science 337(6098):1115–1119. doi:10.1126/science.1225152
Nakagome K, Imamura M, Kawahata K, Harada H, Okunishi K, Matsumoto T, Sasaki O, Tanaka R, Kano MR, Chang H, Hanawa H, Miyazaki J, Yamamoto K, Dohi M (2011) High expression of IL-22 suppresses antigen-induced immune responses and eosinophilic airway inflammation via an IL-10-associated mechanism. J Immunol 187(10):5077–5089. doi:10.4049/jimmunol.1001560
Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M, Asahara H (2008) Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58(5):1284–1292. doi:10.1002/art.23429
Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, Johnson TA, Sun HW, Vahedi G, Hakim O, Handon R, Schwartzberg PL, Hager GL, O’Shea JJ (2011) Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35(6):919–931. doi:10.1016/j.immuni.2011.11.012
Nasu Y, Nishida K, Miyazawa S, Komiyama T, Kadota Y, Abe N, Yoshida A, Hirohata S, Ohtsuka A, Ozaki T (2008) Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage 16(6):723–732. doi:10.1016/j.joca.2007.10.014
Natoli G (2010) Maintaining cell identity through global control of genomic organization. Immunity 33(1):12–24. doi:10.1016/j.immuni.2010.07.006
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534. doi:10.1016/j.cell.2008.11.044
Nishida K, Komiyama T, Miyazawa S, Shen ZN, Furumatsu T, Doi H, Yoshida A, Yamana J, Yamamura M, Ninomiya Y, Inoue H, Asahara H (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50 (10):3365–3376. doi:10.1002/art.20709
Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA 107(33):14751–14756. doi:10.1073/pnas.1003852107
Nistala K, Moncrieffe H, Newton KR, Varsani H, Hunter P, Wedderburn LR (2008) Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum 58(3):875–887. doi:10.1002/art.23291
Noonan JP, McCallion AS (2010) Genomics of long-range regulatory elements. Annu Rev Genomics Hum Genet 11:1–23. doi:10.1146/annurev-genom-082509-141651
Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N, Piolot T, van Berkum NL, Meisig J, Sedat J, Gribnau J, Barillot E, Bluthgen N, Dekker J, Heard E (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485(7398):381–385. doi:10.1038/nature11049
Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C (2009) Bcl6 mediates the development of T follicular helper cells. Science 325(5943):1001–1005. doi:10.1126/science.1176676
Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, Huang H, Wen R, Wang J, Li HS, Watowich SS, Qi H, Dong C, Wang D (2012) STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem 287(14):11234–11239. doi:10.1074/jbc.M111.324046
O’Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D (2010a) MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33(4):607–619. doi:10.1016/j.immuni.2010.09.009
O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D (2010b) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10(2):111–122. doi:10.1038/nri2708
O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327(5969):1098–1102. doi:10.1126/science.1178334
Obokata H, Wakayama T, Sasai Y, Kojima K, Vacanti MP, Niwa H, Yamato M, Vacanti CA (2014) Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature 505(7485):641–647. doi:10.1038/nature12968
Oestreich KJ, Huang AC, Weinmann AS (2011) The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J Exp Med 208(5):1001–1013. doi:10.1084/jem.20102144
Oestreich KJ, Mohn SE, Weinmann AS (2012) 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 13(4):405–411. doi:10.1038/ni.2242
Oh SA, Li MO (2013) TGF-beta: guardian of T cell function. J Immunol 191(8):3973–3979. doi:10.4049/jimmunol.1301843
Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, Huehn J, Fehling HJ, Sparwasser T, Nakai K, Sakaguchi S (2012) T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37(5):785–799. doi:10.1016/j.immuni.2012.09.010
Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38(3):414–423. doi:10.1016/j.immuni.2013.03.002
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
Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19(3):219–220. doi:10.1038/890
Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, Dos Santos L, O’Brien S, Blank R, Lamb E, Natarajan S, Kastenmayer R, Hunter C, Grigg ME, Belkaid Y (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31(5):772–786. doi:10.1016/j.immuni.2009.10.001
Palin AC, Ramachandran V, Acharya S, Lewis DB (2013) Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the microRNA miR-181a. J Immunol 190(6):2682–2691. doi:10.4049/jimmunol.1202534
Pang KC, Dinger ME, Mercer TR, Malquori L, Grimmond SM, Chen W, Mattick JS (2009) Genome-wide identification of long noncoding RNAs in CD8+ T cells. J Immunol 182(12):7738–7748. doi:10.4049/jimmunol.0900603
Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK (2008) Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 10(4):R101. doi:10.1186/ar2493
Peine M, Rausch S, Helmstetter C, Frohlich A, Hegazy AN, Kuhl AA, Grevelding CG, Hofer T, Hartmann S, Lohning M (2013) Stable T-bet(+)GATA-3(+) Th1/Th2 hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation. PLoS Biol 11(8):e1001633. doi:10.1371/journal.pbio.1001633
Phillips-Cremins JE, Sauria ME, Sanyal A, Gerasimova TI, Lajoie BR, Bell JS, Ong CT, Hookway TA, Guo C, Sun Y, Bland MJ, Wagstaff W, Dalton S, McDevitt TC, Sen R, Dekker J, Taylor J, Corces VG (2013) Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153(6):1281–1295. doi:10.1016/j.cell.2013.04.053
Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Weinstein JS, Dong X, Odegard JM, Kaech SM, Dent AL, Crotty S, Craft J (2010) In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol 185(1):313–326. doi:10.4049/jimmunol.0904023
Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38(6):1654–1663
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465(7301):1033–1038. doi:10.1038/nature09144
Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ (2002) The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett 217(2):133–139
Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL, Richardson BC (1993) Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Investig 92(1):38–53. doi:10.1172/JCI116576
Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26(6):841–842. doi:10.1093/bioinformatics/btq033
Rai D, Kim SW, McKeller MR, Dahia PL, Aguiar RC (2010) Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proc Natl Acad Sci USA 107(7):3111–3116. doi:10.1073/pnas.0910667107
Reiner SL, Sallusto F, Lanzavecchia A (2007) Division of labor with a workforce of one: challenges in specifying effector and memory T cell fate. Science 317(5838):622–625
Reinhardt RL, Liang HE, Locksley RM (2009) Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10(4):385–393. doi:10.1038/ni.1715
Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33(11):1665–1673
Rivera CM, Ren B (2013) Mapping human epigenomes. Cell 155(1):39–55. doi:10.1016/j.cell.2013.09.011
Rodriguez-Campos A, Azorin F (2007) RNA is an integral component of chromatin that contributes to its structural organization. PLoS ONE 2(11):e1182. doi:10.1371/journal.pone.0001182
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316(5824):608–611. doi:10.1126/science.1139253
Roncador G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, Ling KL, Pratap S, Toms C, Fox BC, Cerundolo V, Powrie F, Banham AH (2005) Analysis of FOXP3 protein expression in human CD4+ CD25+ regulatory T cells at the single-cell level. Eur J Immunol 35(6):1681–1691. doi:10.1002/eji.200526189
Round JL, Mazmanian SK (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 107(27):12204–12209. doi:10.1073/pnas.0909122107
Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, Benoist C, Rudensky AY (2010) Stability of the regulatory T cell lineage in vivo. Science 329(5999):1667–1671. doi:10.1126/science.1191996
Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241(1):260–268. doi:10.1111/j.1600-065X.2011.01018.x
Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787. doi:10.1016/j.cell.2008.05.009
Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146(3):353–358. doi:10.1016/j.cell.2011.07.014
Samstein RM, Arvey A, Josefowicz SZ, Peng X, Reynolds A, Sandstrom R, Neph S, Sabo P, Kim JM, Liao W, Li MO, Leslie C, Stamatoyannopoulos JA, Rudensky AY (2012) Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151(1):153–166. doi:10.1016/j.cell.2012.06.053
Santangelo S, Cousins DJ, Winkelmann N, Triantaphyllopoulos K, Staynov DZ (2009) Chromatin structure and DNA methylation of the IL-4 gene in human T(H)2 cells. Chromosome Res 17(4):485–496. doi:10.1007/s10577-009-9040-3
Saouaf SJ, Li B, Zhang G, Shen Y, Furuuchi N, Hancock WW, Greene MI (2009) Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis. Exp Mol Pathol 87(2):99–104. doi:10.1016/j.yexmp.2009.06.003
Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C, Sanchez-Gomez DB, Hacisuleyman E, Li E, Spence M, Liapis SC, Mallard W, Morse M, Swerdel MR, D’Ecclessis MF, Moore JC, Lai V, Gong G, Yancopoulos GD, Frendewey D, Kellis M, Hart RP, Valenzuela DM, Arlotta P, Rinn JL (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2:e01749. doi:10.7554/eLife.01749
Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ (2005) IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 201(12):1925–1935. doi:10.1084/jem.20050419
Schmidl C, Hansmann L, Andreesen R, Edinger M, Hoffmann P, Rehli M (2011) Epigenetic reprogramming of the RORC locus during in vitro expansion is a distinctive feature of human memory but not naive Treg. Eur J Immunol 41(5):1491–1498. doi:10.1002/eji.201041067
Schmitt N, Bustamante J, Bourdery L, Bentebibel SE, Boisson-Dupuis S, Hamlin F, Tran MV, Blankenship D, Pascual V, Savino DA, Banchereau J, Casanova JL, Ueno H (2013) IL-12 receptor beta1 deficiency alters in vivo T follicular helper cell response in humans. Blood 121(17):3375–3385. doi:10.1182/blood-2012-08-448902
Schneider C, King RM, Philipson L (1988) Genes specifically expressed at growth arrest of mammalian cells. Cell 54(6):787–793
Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, Stamatoyannopoulos JA, Wilson CB (2007) Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol 8(7):732–742
Sekimata M, Perez-Melgosa M, Miller SA, Weinmann AS, Sabo PJ, Sandstrom R, Dorschner MO, Stamatoyannopoulos JA, Wilson CB (2009) CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus. Immunity 31(4):551–564. doi:10.1016/j.immuni.2009.08.021
Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL, Shi H, Munn DH (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38(5):998–1012. doi:10.1016/j.immuni.2013.01.013
Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, Li Z, Schmidt V, Hogan PG, Sacks DB, Rao A (2011) Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci USA 108(28):11381–11386. doi:10.1073/pnas.1019711108
Sheik Mohamed J, Gaughwin PM, Lim B, Robson P, Lipovich L (2010) Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA 16(2):324–337. doi:10.1261/rna.1441510
Shevach EM (2000) Regulatory T cells in autoimmmunity*. Annu Rev Immunol 18:423–449
Smith K, McCoy KD, Macpherson AJ (2007) Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 19(2):59–69. doi:10.1016/j.smim.2006.10.002
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341(6145):569–573. doi:10.1126/science.1241165
Sonkoly E, Janson P, Majuri ML, Savinko T, Fyhrquist N, Eidsmo L, Xu N, Meisgen F, Wei T, Bradley M, Stenvang J, Kauppinen S, Alenius H, Lauerma A, Homey B, Winqvist O, Stahle M, Pivarcsi A (2010) MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4. J Allergy Clin Immunol 126 (3):581–589 e581–520. doi:10.1016/j.jaci.2010.05.045
Spilianakis CG, Flavell RA (2004) Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat Immunol 5(10):1017–1027. doi:10.1038/ni1115
Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA (2005) Interchromosomal associations between alternatively expressed loci. Nature 435(7042):637–645. doi:10.1038/nature03574
Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33(2):192–202. doi:10.1016/j.immuni.2010.07.014
Steinman L (2007) A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 13(2):139–145. doi:10.1038/nm1551
Stock P, Akbari O, Berry G, Freeman GJ, Dekruyff RH, Umetsu DT (2004) Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol 5(11):1149–1156. doi:10.1038/ni1122
Stockinger B, Veldhoen M, Martin B (2007) Th17 T cells: linking innate and adaptive immunity. Semin Immunol 19(6):353–361. doi:10.1016/j.smim.2007.10.008
Szabo SJ, Dighe AS, Gubler U, Murphy KM (1997) Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 185(5):817–824
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100(6):655–669
Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G, Muljo SA, Kuchen S, Casellas R, Wei L, Kanno Y, O’Shea JJ (2012) TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol 13(6):587–595. doi:10.1038/ni.2286
Tang Y, Luo X, Cui H, Ni X, Yuan M, Guo Y, Huang X, Zhou H, de Vries N, Tak PP, Chen S, Shen N (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60(4):1065–1075. doi:10.1002/art.24436
Thomas RM, Gamper CJ, Ladle BH, Powell JD, Wells AD (2012) De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem 287(27):22900–22909. doi:10.1074/jbc.M111.312785
Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184(7):3433–3441. doi:10.4049/jimmunol.0904028
Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 10(8):864–871. doi:10.1038/ni.1770
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. doi:10.1016/j.immuni.2013.09.012
Umesaki Y, Setoyama H, Matsumoto S, Imaoka A, Itoh K (1999) Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system. Infect Immun 67(7):3504–3511
Usui T, Nishikomori R, Kitani A, Strober W (2003) GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rbeta2 chain or T-bet. Immunity 18(3):415–428
van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CP, Pals CE, Meerding J, Berkers CR, Barbi J, Grone A, Sijts AJ, Maurice MM, Kalkhoven E, Prakken BJ, Ovaa H, Pan F, Zaiss DM, Coffer PJ (2013) Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39(2):259–271. doi:10.1016/j.immuni.2013.05.018
Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206(1):43–49. doi:10.1084/jem.20081438
Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109. doi:10.1038/nature06881
Veldhoen Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346
Vigneau S, Rohrlich PS, Brahic M, Bureau JF (2003) Tmevpg1, a candidate gene for the control of Theiler’s virus persistence, could be implicated in the regulation of gamma interferon. J Virol 77(10):5632–5638
Vojinovic J, Damjanov N, D’Urzo C, Furlan A, Susic G, Pasic S, Iagaru N, Stefan M, Dinarello CA (2011) Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 63(5):1452–1458. doi:10.1002/art.30238
Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, Arima K, Bover L, Hanabuchi S, Khalili J, Marinova E, Zheng B, Littman DR, Liu YJ (2009) Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 106(12):4793–4798
Wang A, Pan D, Lee YH, Martinez GJ, Feng XH, Dong C (2013) Cutting edge: Smad2 and Smad4 regulate TGF-beta-mediated Il9 gene expression via EZH2 displacement. J Immunol 191(10):4908–4912. doi:10.4049/jimmunol.1300433
Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA, Glass CK, Rosenfeld MG, Fu XD (2011a) Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474(7351):390–394. doi:10.1038/nature10006
Wang G, Kwan BC, Lai FM, Chow KM, Li PK, Szeto CC (2011b) Elevated levels of miR-146a and miR-155 in kidney biopsy and urine from patients with IgA nephropathy. Dis Markers 30(4):171–179. doi:10.3233/DMA-2011-0766
Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR (2011c) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35(6):871–882. doi:10.1016/j.immuni.2011.09.021
Wang Y, Su MA, Wan YY (2011d) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35(3):337–348. doi:10.1016/j.immuni.2011.08.012
Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE (2007) Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 37(1):129–138. doi:10.1002/eji.200636435
Wang L, de Zoeten EF, Greene MI, Hancock WW (2009a) Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3 + regulatory T cells. Nat Rev Drug Discov 8(12):969–981. doi:10.1038/nrd3031
Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K (2009b) Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138(5):1019–1031. doi:10.1016/j.cell.2009.06.049
Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852. doi:10.1146/annurev.immunol.25.022106.141557
Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT, Schones DE, Peng W, Sun HW, Paul WE, O’Shea JJ, Zhao K (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30(1):155–167
Weiner HL, da Cunha AP, Quintana F, Wu H (2011) Oral tolerance. Immunol Rev 241(1):241–259. doi:10.1111/j.1600-065X.2011.01017.x
Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG (2005) A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309(5740):1570–1573. doi:10.1126/science.1115901
Wilson CB, Rowell E, Sekimata M (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9(2):91–105
Winders BR, Schwartz RH, Bruniquel D (2004) A distinct region of the murine IFN-gamma promoter is hypomethylated from early T cell development through mature naive and Th1 cell differentiation, but is hypermethylated in Th2 cells. J Immunol 173(12):7377–7384
Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R, Paul WE, Bosselut R, Wei G, Zhao K, Oukka M, Zhu J, Belkaid Y (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Investig 121(11):4503–4515. doi:10.1172/JCI57456
Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496(7446):513–517. doi:10.1038/nature11984
Xu L, Kitani A, Stuelten C, McGrady G, Fuss I, Strober W (2010) Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 33(3):313–325. doi:10.1016/j.immuni.2010.09.001
Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, Ruminski P, Weiss D, Von Schack D, Bluestone JA (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209 (10):1713–1722, S1711–1719. doi:10.1084/jem.20120822
Yamanaka S, Blau HM (2010) Nuclear reprogramming to a pluripotent state by three approaches. Nature 465(7299):704–712. doi:10.1038/nature09229
Yamane H, Paul WE (2012) Memory CD4 + T cells: fate determination, positive feedback and plasticity. Cell Mol Life Sci 69(10):1577–1583. doi:10.1007/s00018-012-0966-9
Yang L, Boldin MP, Yu Y, Liu CS, Ea CK, Ramakrishnan P, Taganov KD, Zhao JL, Baltimore D (2012) miR-146a controls the resolution of T cell responses in mice. J Exp Med 209(9):1655–1670. doi:10.1084/jem.20112218
Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C (2008a) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29(1):44–56
Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008b) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28(1):29–39. doi:10.1016/j.immuni.2007.11.016
Yang XP, Ghoreschi K, Steward-Tharp SM, Rodriguez-Canales J, Zhu J, Grainger JR, Hirahara K, Sun HW, Wei L, Vahedi G, Kanno Y, O’Shea JJ, Laurence A (2011) Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 12(3):247–254. doi:10.1038/ni.1995
Yosef N, Shalek AK, Gaublomme JT, Jin H, Lee Y, Awasthi A, Wu C, Karwacz K, Xiao S, Jorgolli M, Gennert D, Satija R, Shakya A, Lu DY, Trombetta JJ, Pillai MR, Ratcliffe PJ, Coleman ML, Bix M, Tantin D, Park H, Kuchroo VK, Regev A (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496(7446):461–468. doi:10.1038/nature11981
Young HA, Ghosh P, Ye J, Lederer J, Lichtman A, Gerard JR, Penix L, Wilson CB, Melvin AJ, McGurn ME et al (1994) Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene. J Immunol 153(8):3603–3610
Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma CS, Li QJ, Parish CR, Mackay CR, Vinuesa CG (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31(3):457–468. doi:10.1016/j.immuni.2009.07.002
Zhang DH, Cohn L, Ray P, Bottomly K, Ray A (1997) Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 272(34):21597–21603
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):808–812. doi:10.1038/nature08750
Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY (2007) Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445(7130):936–940. doi:10.1038/nature05563
Zheng Y, Rudensky AY (2007) Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8(5):457–462
Zhou L, Chong MM, Littman DR (2009a) Plasticity of CD4 + T cell lineage differentiation. Immunity 30(5):646–655
Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8(9):967–974
Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240
Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, Nakayama M, Rosenthal W, Bluestone JA (2009b) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10(9):1000–1007. doi:10.1038/ni.1774
Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238(1):247–262. doi:10.1111/j.1600-065X.2010.00951.x
Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489. doi:10.1146/annurev-immunol-030409-101212
Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, Monticelli S, Lanzavecchia A, Sallusto F (2012) Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 484(7395):514–518. doi:10.1038/nature10957
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Bonelli, M. et al. (2014). Helper T Cell Plasticity: Impact of Extrinsic and Intrinsic Signals on Transcriptomes and Epigenomes. In: Ellmeier, W., Taniuchi, I. (eds) Transcriptional Control of Lineage Differentiation in Immune Cells. Current Topics in Microbiology and Immunology, vol 381. Springer, Cham. https://doi.org/10.1007/82_2014_371
Download citation
DOI: https://doi.org/10.1007/82_2014_371
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-07394-1
Online ISBN: 978-3-319-07395-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)