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Regulation of IL-4 Expression in Immunity and Diseases

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Regulation of Cytokine Gene Expression in Immunity and Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 941))

Abstract

IL-4 was first identified as a T cell-derived growth factor for B cells. Studies over the past several decades have markedly expanded our understanding of its cellular sources and function. In addition to T cells, IL-4 is produced by innate lymphocytes, such as NTK cells, and myeloid cells, such as basophils and mast cells. It is a signature cytokine of type 2 immune response but also has a nonimmune function. Its expression is tightly regulated at several levels, including signaling pathways, transcription factors, epigenetic modifications, microRNA, and long noncoding RNA. This chapter will review in detail the molecular mechanism regulating the cell type-specific expression of IL-4 in physiological and pathological type 2 immune responses.

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References

  1. Howard M, et al. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982;155:914–23.

    Article  CAS  PubMed  Google Scholar 

  2. Isakson PC, Pure E, Vitetta ES, Krammer PH. T cell-derived B cell differentiation factor(s). Effect on the isotype switch of murine B cells. J Exp Med. 1982;155:734–48.

    Article  CAS  PubMed  Google Scholar 

  3. Lee F, et al. Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986;83:2061–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Noma Y, et al. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986;319:640–6. doi:10.1038/319640a0.

    Article  CAS  PubMed  Google Scholar 

  5. Carr C, Aykent S, Kimack NM, Levine AD. Disulfide assignments in recombinant mouse and human interleukin 4. Biochemistry. 1991;30:1515–23.

    Article  CAS  PubMed  Google Scholar 

  6. Walter MR, et al. Crystal structure of recombinant human interleukin-4. J Biol Chem. 1992;267:20371–6.

    CAS  PubMed  Google Scholar 

  7. Wlodawer A, Pavlovsky A, Gustchina A. Crystal structure of human recombinant interleukin-4 at 2.25 A resolution. FEBS Lett. 1992;309:59–64.

    Article  CAS  PubMed  Google Scholar 

  8. Smith LJ, et al. Human interleukin 4. The solution structure of a four-helix bundle protein. J Mol Biol. 1992;224:899–904.

    Article  CAS  PubMed  Google Scholar 

  9. Powers R, et al. Three-dimensional solution structure of human interleukin-4 by multidimensional heteronuclear magnetic resonance spectroscopy. Science. 1992;256:1673–7.

    Article  CAS  PubMed  Google Scholar 

  10. Schmitt N, Ueno H. Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol. 2015;34:130–6. doi:10.1016/j.coi.2015.03.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41:529–42. doi:10.1016/j.immuni.2014.10.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Johnston RJ, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325:1006–10. doi:10.1126/science.1175870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu D, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009;31:457–68. doi:10.1016/j.immuni.2009.07.002.

    Article  CAS  PubMed  Google Scholar 

  14. Nurieva RI, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325:1001–5. doi:10.1126/science.1176676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Riviere I, Sunshine MJ, Littman DR. Regulation of IL-4 expression by activation of individual alleles. Immunity. 1998;9:217–28.

    Article  CAS  PubMed  Google Scholar 

  16. Ho IC, Kaplan MH, Jackson-Grusby L, Glimcher LH, Grusby MJ. Marking IL-4-producing cells by knock-in of the IL-4 gene. Int Immunol. 1999;11:243–7.

    Article  CAS  PubMed  Google Scholar 

  17. Hu-Li J, et al. Regulation of expression of IL-4 alleles: analysis using a chimeric GFP/IL-4 gene. Immunity. 2001;14:1–11.

    Article  CAS  PubMed  Google Scholar 

  18. Mohrs K, Wakil AE, Killeen N, Locksley RM, Mohrs M. A two-step process for cytokine production revealed by IL-4 dual-reporter mice. Immunity. 2005;23:419–29. doi:10.1016/j.immuni.2005.09.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gessner A, Mohrs K, Mohrs M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J Immunol. 2005;174:1063–72.

    Article  CAS  PubMed  Google Scholar 

  20. Mohrs K, Harris DP, Lund FE, Mohrs M. Systemic dissemination and persistence of Th2 and type 2 cells in response to infection with a strictly enteric nematode parasite. J Immunol. 2005;175:5306–13.

    Article  CAS  PubMed  Google Scholar 

  21. Wang T, Secombes CJ. The evolution of IL-4 and IL-13 and their receptor subunits. Cytokine. 2015. doi:10.1016/j.cyto.2015.04.012.

    Google Scholar 

  22. Munitz A, Brandt EB, Mingler M, Finkelman FD, Rothenberg ME. Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci U S A. 2008;105:7240–5. doi:10.1073/pnas.0802465105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Junttila IS, et al. Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity. J Exp Med. 2008;205:2595–608. doi:10.1084/jem.20080452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ramalingam TR, et al. Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain. Nat Immunol. 2008;9:25–33. doi:10.1038/ni1544.

    Article  CAS  PubMed  Google Scholar 

  25. Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011;50:87–96. doi:10.1007/s12026-011-8205-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Heller NM, et al. Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages. Sci Signal. 2008;1:ra17. doi:10.1126/scisignal.1164795.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Stephenson LM, Park DS, Mora AL, Goenka S, Boothby M. Sequence motifs in IL-4R alpha mediating cell-cycle progression of primary lymphocytes. J Immunol. 2005;175:5178–85.

    Article  CAS  PubMed  Google Scholar 

  28. Vazquez MI, Catalan-Dibene J, Zlotnik A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine. 2015;74:318–26. doi:10.1016/j.cyto.2015.02.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gauchat JF, et al. A novel 4-kb interleukin-13 receptor alpha mRNA expressed in human B, T, and endothelial cells encoding an alternate type-II interleukin-4/interleukin-13 receptor. Eur J Immunol. 1997;27:971–8. doi:10.1002/eji.1830270425.

    Article  CAS  PubMed  Google Scholar 

  30. Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994;15:19–26. doi:10.1016/0167-5699(94)90021-3.

    Article  CAS  PubMed  Google Scholar 

  31. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev. 2008;8:958–69.

    CAS  Google Scholar 

  33. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med. 1992;176:287–92.

    Article  CAS  PubMed  Google Scholar 

  34. Doherty TM, Kastelein R, Menon S, Andrade S, Coffman RL. Modulation of murine macrophage function by IL-13. J Immunol. 1993;151:7151–60.

    CAS  PubMed  Google Scholar 

  35. Banks EM, Coleman JW. A comparative study of peritoneal mast cells from mutant IL-4 deficient and normal mice: evidence that IL-4 is not essential for mast cell development but enhances secretion via control of IgE binding and passive sensitization. Cytokine. 1996;8:190–6. doi:10.1006/cyto.1996.0027.

    Article  CAS  PubMed  Google Scholar 

  36. McLeod JJ, Baker B, Ryan JJ. Mast cell production and response to IL-4 and IL-13. Cytokine. 2015. doi:10.1016/j.cyto.2015.05.019.

    PubMed  PubMed Central  Google Scholar 

  37. Chen XJ, Lycke N, Enerback L. Surface and gene expression of immunoglobulin E receptors on mast cells and mast-cell numbers in interleukin-4-gene knockout mice. Immunology. 1999;96:544–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamaguchi M, et al. IgE enhances Fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fc epsilon receptor I expression and mediator release. J Immunol. 1999;162:5455–65.

    CAS  PubMed  Google Scholar 

  39. Marcais A, et al. Regulation of mouse NK cell development and function by cytokines. Front Immunol. 2013;4:450. doi:10.3389/fimmu.2013.00450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Lee YJ, Jameson SC, Hogquist KA. Alternative memory in the CD8 T cell lineage. Trends Immunol. 2011;32:50–6. doi:10.1016/j.it.2010.12.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Weinreich MA, Odumade OA, Jameson SC, Hogquist KA. T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat Immunol. 2010;11:709–16. doi:10.1038/ni.1898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gordon SM, et al. Requirements for eomesodermin and promyelocytic leukemia zinc finger in the development of innate-like CD8+ T cells. J Immunol. 2011;186:4573–8. doi:10.4049/jimmunol.1100037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lai D, et al. KLF13 sustains thymic memory-like CD8(+) T cells in BALB/c mice by regulating IL-4-generating invariant natural killer T cells. J Exp Med. 2011;208:1093–103. doi:10.1084/jem.20101527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Carty SA, Koretzky GA, Jordan MS. Interleukin-4 regulates eomesodermin in CD8+ T cell development and differentiation. PLoS One. 2014;9:e106659. doi:10.1371/journal.pone.0106659.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Pulendran B, Artis D. New paradigms in type 2 immunity. Science. 2012;337:431–5. doi:10.1126/science.1221064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Urban Jr JF, Maliszewski CR, Madden KB, Katona IM, Finkelman FD. IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice. J Immunol. 1995;154:4675–84.

    CAS  PubMed  Google Scholar 

  47. Grunig G, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998;282:2261–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bancroft AJ, McKenzie AN, Grencis RK. A critical role for IL-13 in resistance to intestinal nematode infection. J Immunol. 1998;160:3453–61.

    CAS  PubMed  Google Scholar 

  49. Urban Jr JF, Katona IM, Paul WE, Finkelman FD. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc Natl Acad Sci U S A. 1991;88:5513–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brusselle GG, et al. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 1994;24:73–80.

    Article  CAS  Google Scholar 

  51. Corry DB, et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996;183:109–17.

    Article  CAS  PubMed  Google Scholar 

  52. Rankin JA, et al. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci U S A. 1996;93:7821–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wills-Karp M, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282:2258–61.

    Article  CAS  PubMed  Google Scholar 

  54. Urban Jr JF, et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity. 1998;8:255–64.

    Article  CAS  PubMed  Google Scholar 

  55. Shin K, et al. TH2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat Commun. 2015;6:6196. doi:10.1038/ncomms7196.

    Article  CAS  PubMed  Google Scholar 

  56. Savetsky IL, et al. Th2 cytokines inhibit lymphangiogenesis. PLoS One. 2015;10:e0126908. doi:10.1371/journal.pone.0126908.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Walsh JT, et al. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest. 2015;125:699–714. doi:10.1172/JCI76210.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Karp CL, Murray PJ. Non-canonical alternatives: what a macrophage is 4. J Exp Med. 2012;209:427–31. doi:10.1084/jem.20120295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nguyen KD, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480:104–8. doi:10.1038/nature10653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tsao CH, Shiau MY, Chuang PH, Chang YH, Hwang J. Interleukin-4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis. J Lipid Res. 2014;55:385–97. doi:10.1194/jlr.M041392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wu D, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011;332:243–7. doi:10.1126/science.1201475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Qiu Y, et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell. 2014;157:1292–308. doi:10.1016/j.cell.2014.03.066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rao RR, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell. 2014;157:1279–91. doi:10.1016/j.cell.2014.03.065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li-Weber M, Krammer PH. Regulation of IL4 gene expression by T cells and therapeutic perspectives. Nat Rev Immunol. 2003;3:534–43. doi:10.1038/nri1128.

    Article  CAS  PubMed  Google Scholar 

  65. Takemoto N, et al. Th2-specific DNase I-hypersensitive sites in the murine IL-13 and IL-4 intergenic region. Int Immunol. 1998;10:1981–5.

    Article  CAS  PubMed  Google Scholar 

  66. Loots GG, et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science. 2000;288:136–40.

    Article  CAS  PubMed  Google Scholar 

  67. Takemoto N, et al. Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster. J Immunol. 2000;165:6687–91.

    Article  CAS  PubMed  Google Scholar 

  68. Mohrs M, et al. Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat Immunol. 2001;2:842–7. doi:10.1038/ni0901-842.

    Article  CAS  PubMed  Google Scholar 

  69. Tanaka S, et al. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells. Nat Immunol. 2011;12:77–85. doi:10.1038/ni.1966.

    Article  CAS  PubMed  Google Scholar 

  70. Henkel G, et al. A DNase I-hypersensitive site in the second intron of the murine IL-4 gene defines a mast cell-specific enhancer. J Immunol. 1992;149:3239–46.

    CAS  PubMed  Google Scholar 

  71. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity. 1998;9:765–75.

    Article  CAS  PubMed  Google Scholar 

  72. Lee GR, Fields PE, Flavell RA. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity. 2001;14:447–59.

    Article  CAS  PubMed  Google Scholar 

  73. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity. 2003;19:739–48.

    Article  CAS  PubMed  Google Scholar 

  74. Agarwal S, Avni O, Rao A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity. 2000;12:643–52.

    Article  CAS  PubMed  Google Scholar 

  75. Guo L, Hu-Li J, Paul WE. Probabilistic regulation of IL-4 production in Th2 cells: accessibility at the Il4 locus. Immunity. 2004;20:193–203.

    Article  CAS  PubMed  Google Scholar 

  76. Kock J, et al. Nuclear factor of activated T cells regulates the expression of interleukin-4 in Th2 cells in an all-or-none fashion. J Biol Chem. 2014;289:26752–61. doi:10.1074/jbc.M114.587865.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Tanaka S, et al. The interleukin-4 enhancer CNS-2 is regulated by Notch signals and controls initial expression in NKT cells and memory-type CD4 T cells. Immunity. 2006;24:689–701. doi:10.1016/j.immuni.2006.04.009.

    Article  CAS  PubMed  Google Scholar 

  78. Solymar DC, Agarwal S, Bassing CH, Alt FW, Rao A. A 3′ enhancer in the IL-4 gene regulates cytokine production by Th2 cells and mast cells. Immunity. 2002;17:41–50.

    Article  CAS  PubMed  Google Scholar 

  79. 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. doi:10.1016/j.immuni.2012.02.002.

    Article  CAS  PubMed  Google Scholar 

  80. Vijayanand P, et al. Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity. 2012;36:175–87. doi:10.1016/j.immuni.2011.12.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yagi R, Tanaka S, Motomura Y, Kubo M. Regulation of the Il4 gene is independently controlled by proximal and distal 3′ enhancers in mast cells and basophils. Mol Cell Biol. 2007;27:8087–97. doi:10.1128/MCB.00631-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Djuretic IM, et al. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol. 2007;8:145–53. doi:10.1038/ni1424.

    Article  CAS  PubMed  Google Scholar 

  83. Lee GR, Fields PE, Griffin TJ, Flavell RA. Regulation of the Th2 cytokine locus by a locus control region. Immunity. 2003;19:145–53.

    Article  CAS  PubMed  Google Scholar 

  84. Koh BH, et al. Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma. Proc Natl Acad Sci U S A. 2010;107:10614–9. doi:10.1073/pnas.1005383107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fields PE, Lee GR, Kim ST, Bartsevich VV, Flavell RA. Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity. 2004;21:865–76. doi:10.1016/j.immuni.2004.10.015.

    Article  CAS  PubMed  Google Scholar 

  86. Lee DU, Rao A. Molecular analysis of a locus control region in the T helper 2 cytokine gene cluster: a target for STAT6 but not GATA3. Proc Natl Acad Sci U S A. 2004;101:16010–5. doi:10.1073/pnas.0407031101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Spilianakis CG, Flavell RA. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat Immunol. 2004;5:1017–27. doi:10.1038/ni1115.

    Article  CAS  PubMed  Google Scholar 

  88. Lee GR, Spilianakis CG, Flavell RA. Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions. Nat Immunol. 2005;6:42–8. doi:10.1038/ni1148.

    Article  CAS  PubMed  Google Scholar 

  89. Williams A, et al. Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression. Proc Natl Acad Sci U S A. 2013;110:6955–60. doi:10.1073/pnas.1304720110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kubo M, et al. T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6. EMBO J. 1997;16:4007–20. doi:10.1093/emboj/16.13.4007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ansel KM, et al. Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity. Nat Immunol. 2004;5:1251–9. doi:10.1038/ni1135.

    Article  CAS  PubMed  Google Scholar 

  92. Blonska M, Joo D, Zweidler-McKay PA, Zhao Q, Lin X. CARMA1 controls Th2 cell-specific cytokine expression through regulating JunB and GATA3 transcription factors. J Immunol. 2012;188:3160–8. doi:10.4049/jimmunol.1102943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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;182:1579–84.

    Article  CAS  PubMed  Google Scholar 

  94. Pfeiffer C, et al. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995;181:1569–74.

    Article  CAS  PubMed  Google Scholar 

  95. Constant S, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J Exp Med. 1995;182:1591–6.

    Article  CAS  PubMed  Google Scholar 

  96. Jorritsma PJ, Brogdon JL, Bottomly K. Role of TCR-induced extracellular signal-regulated kinase activation in the regulation of early IL-4 expression in naive CD4+ T cells. J Immunol. 2003;170:2427–34.

    Article  CAS  PubMed  Google Scholar 

  97. Elo LL, et al. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity. 2010;32:852–62. doi:10.1016/j.immuni.2010.06.011.

    Article  CAS  PubMed  Google Scholar 

  98. Kaplan MH, Wurster AL, Smiley ST, Grusby MJ. Stat6-dependent and -independent pathways for IL-4 production. J Immunol. 1999;163:6536–40.

    CAS  PubMed  Google Scholar 

  99. van Panhuys N, et al. Basophils are the major producers of IL-4 during primary helminth infection. J Immunol. 2011;186:2719–28. doi:10.4049/jimmunol.1000940.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Stokes K, et al. Cutting edge: STAT6 signaling in eosinophils is necessary for development of allergic airway inflammation. J Immunol. 2015;194:2477–81. doi:10.4049/jimmunol.1402096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4:313–9.

    Article  CAS  PubMed  Google Scholar 

  102. Shimoda K, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996;380:630–3. doi:10.1038/380630a0.

    Article  CAS  PubMed  Google Scholar 

  103. Takeda K, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996;380:627–30. doi:10.1038/380627a0.

    Article  CAS  PubMed  Google Scholar 

  104. Kurata H, Lee HJ, O’Garra A, Arai N. Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity. 1999;11:677–88.

    Article  CAS  PubMed  Google Scholar 

  105. Hanson EM, Dickensheets H, Qu CK, Donnelly RP, Keegan AD. Regulation of the dephosphorylation of Stat6. Participation of Tyr-713 in the interleukin-4 receptor alpha, the tyrosine phosphatase SHP-1, and the proteasome. J Biol Chem. 2003;278:3903–11. doi:10.1074/jbc.M211747200.

    Article  CAS  PubMed  Google Scholar 

  106. Johnson DJ, et al. Shp1 regulates T cell homeostasis by limiting IL-4 signals. J Exp Med. 2013;210:1419–31. doi:10.1084/jem.20122239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sahoo A, Alekseev A, Obertas L, Nurieva R. Grail controls Th2 cell development by targeting STAT6 for degradation. Nat Commun. 2014;5:4732. doi:10.1038/ncomms5732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ouyang W, et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity. 2000;12:27–37.

    Article  CAS  PubMed  Google Scholar 

  109. Asnagli H, Afkarian M, Murphy KM. Cutting edge: identification of an alternative GATA-3 promoter directing tissue-specific gene expression in mouse and human. J Immunol. 2002;168:4268–71.

    Article  CAS  PubMed  Google Scholar 

  110. Scheinman EJ, Avni O. Transcriptional regulation of GATA3 in T helper cells by the integrated activities of transcription factors downstream of the interleukin-4 receptor and T cell receptor. J Biol Chem. 2009;284:3037–48. doi:10.1074/jbc.M807302200.

    Article  CAS  PubMed  Google Scholar 

  111. Cai S, Lee CC, Kohwi-Shigematsu T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet. 2006;38:1278–88. doi:10.1038/ng1913.

    Article  CAS  PubMed  Google Scholar 

  112. Kim ST, Fields PE, Flavell RA. Demethylation of a specific hypersensitive site in the Th2 locus control region. Proc Natl Acad Sci U S A. 2007;104:17052–7. doi:10.1073/pnas.0708293104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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;32:840–51. doi:10.1016/j.immuni.2010.06.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Finkelman FD, et al. Stat6 regulation of in vivo IL-4 responses. J Immunol. 2000;164:2303–10.

    Article  CAS  PubMed  Google Scholar 

  115. Voehringer D, Shinkai K, Locksley RM. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity. 2004;20:267–77.

    Article  CAS  PubMed  Google Scholar 

  116. Liang HE, et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol. 2012;13:58–66. doi:10.1038/ni.2182.

    Article  CAS  Google Scholar 

  117. 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;105:12423–8. doi:10.1073/pnas.0806372105.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Jankovic D, et al. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile. J Immunol. 2000;164:3047–55.

    Article  CAS  PubMed  Google Scholar 

  119. Hwang ES, White IA, Ho IC. An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines. Proc Natl Acad Sci U S A. 2002;99:13026–30. doi:10.1073/pnas.202474499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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;145:1127–36.

    CAS  PubMed  Google Scholar 

  121. Cote-Sierra J, et al. Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci U S A. 2004;101:3880–5. doi:10.1073/pnas.0400339101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kagami S, et al. Both stat5a and stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue. Blood. 2000;95:1370–7.

    CAS  PubMed  Google Scholar 

  123. Takatori H, et al. Indispensable role of Stat5a in Stat6-independent Th2 cell differentiation and allergic airway inflammation. J Immunol. 2005;174:3734–40.

    Article  CAS  PubMed  Google Scholar 

  124. Zhu J, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004;5:1157–65. doi:10.1038/ni1128.

    Article  CAS  PubMed  Google Scholar 

  125. Rani A, et al. IL-2 regulates expression of C-MAF in human CD4 T cells. J Immunol. 2011;187:3721–9. doi:10.4049/jimmunol.1002354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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;9:1288–96. doi:10.1038/ni.1656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mukherjee S, et al. STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease. J Immunol. 2014;192:996–1003. doi:10.4049/jimmunol.1301991.

    Article  CAS  PubMed  Google Scholar 

  128. Adler SH, et al. Notch signaling augments T cell responsiveness by enhancing CD25 expression. J Immunol. 2003;171:2896–903.

    Article  CAS  PubMed  Google Scholar 

  129. Takatori H, et al. Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression. J Immunol. 2005;174:4105–12.

    Article  CAS  PubMed  Google Scholar 

  130. Bruchard M, et al. The receptor NLRP3 is a transcriptional regulator of T2 differentiation. Nat Immunol. 2015. doi:10.1038/ni.3202.

    Google Scholar 

  131. Radtke F, MacDonald HR, Tacchini-Cottier F. Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol. 2013;13:427–37. doi:10.1038/nri3445.

    Article  CAS  PubMed  Google Scholar 

  132. Tanigaki K, et al. Regulation of alphabeta/gammadelta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity. 2004;20:611–22.

    Article  CAS  PubMed  Google Scholar 

  133. Amsen D, et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity. 2007;27:89–99. doi:10.1016/j.immuni.2007.05.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Amsen D, et al. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell. 2004;117:515–26.

    Article  CAS  PubMed  Google Scholar 

  135. Fang TC, et al. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity. 2007;27:100–10. doi:10.1016/j.immuni.2007.04.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Tu L, et al. Notch signaling is an important regulator of type 2 immunity. J Exp Med. 2005;202:1037–42. doi:10.1084/jem.20050923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Skokos D, Nussenzweig MC. CD8- DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. J Exp Med. 2007;204:1525–31. doi:10.1084/jem.20062305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Maekawa Y, et al. Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity. 2003;19:549–59.

    Article  CAS  PubMed  Google Scholar 

  139. Sun J, Krawczyk CJ, Pearce EJ. Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. J Immunol. 2008;180:1655–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Ong CT, Sedy JR, Murphy KM, Kopan R. Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition. PLoS One. 2008;3:e2823. doi:10.1371/journal.pone.0002823.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Krawczyk CM, Sun J, Pearce EJ. Th2 differentiation is unaffected by Jagged2 expression on dendritic cells. J Immunol. 2008;180:7931–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Bailis W, et al. Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity. 2013;39:148–59. doi:10.1016/j.immuni.2013.07.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol. 2008;8:581–93. doi:10.1038/nri2360.

    Article  CAS  PubMed  Google Scholar 

  144. Notani D, et al. Global regulator SATB1 recruits beta-catenin and regulates T(H)2 differentiation in Wnt-dependent manner. PLoS Biol. 2010;8:e1000296. doi:10.1371/journal.pbio.1000296.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Yu Q, et al. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma. Nat Immunol. 2009;10:992–9. doi:10.1038/ni.1762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Maier E, et al. Inhibition of suppressive T cell factor 1 (TCF-1) isoforms in naive CD4+ T cells is mediated by IL-4/STAT6 signaling. J Biol Chem. 2011;286:919–28. doi:10.1074/jbc.M110.144949.

    Article  CAS  PubMed  Google Scholar 

  147. Hossain MB, et al. Lymphoid enhancer factor interacts with GATA-3 and controls its function in T helper type 2 cells. Immunology. 2008;125:377–86. doi:10.1111/j.1365-2567.2008.02854.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hebenstreit D, et al. LEF-1 negatively controls interleukin-4 expression through a proximal promoter regulatory element. J Biol Chem. 2008;283:22490–7. doi:10.1074/jbc.M804096200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Albert V, Hall MN. mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol. 2015;33:55–66. doi:10.1016/j.ceb.2014.12.001.

    Article  CAS  PubMed  Google Scholar 

  150. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell. 2011;144:757–68. doi:10.1016/j.cell.2011.02.014.

    Article  CAS  PubMed  Google Scholar 

  151. Delgoffe GM, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44. doi:10.1016/j.immuni.2009.04.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Delgoffe GM, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295–303. doi:10.1038/ni.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lee K, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity. 2010;32:743–53. doi:10.1016/j.immuni.2010.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yang K, et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity. 2013;39:1043–56. doi:10.1016/j.immuni.2013.09.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Heikamp EB, et al. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol. 2014;15:457–64. doi:10.1038/ni.2867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Imanishi T, et al. Nucleic acid sensing by T cells initiates Th2 cell differentiation. Nat Commun. 2014;5:3566. doi:10.1038/ncomms4566.

    Article  PubMed  CAS  Google Scholar 

  157. Ho IC, et al. Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor alpha gene. EMBO J. 1991;10:1187–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Ko LJ, et al. Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer. Mol Cell Biol. 1991;11:2778–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ting CN, Olson MC, Barton KP, Leiden JM. Transcription factor GATA-3 is required for development of the T-cell lineage. Nature. 1996;384:474–8. doi:10.1038/384474a0.

    Article  CAS  PubMed  Google Scholar 

  160. Pai SY, et al. Critical roles for transcription factor GATA-3 in thymocyte development. Immunity. 2003;19:863–75.

    Article  CAS  PubMed  Google Scholar 

  161. Tindemans I, Serafini N, Di Santo JP, Hendriks RW. GATA-3 function in innate and adaptive immunity. Immunity. 2014;41:191–206. doi:10.1016/j.immuni.2014.06.006.

    Article  CAS  PubMed  Google Scholar 

  162. Kim PJ, et al. GATA-3 regulates the development and function of invariant NKT cells. J Immunol. 2006;177:6650–9.

    Article  CAS  PubMed  Google Scholar 

  163. Tai TS, Pai SY, Ho IC. GATA-3 regulates the homeostasis and activation of CD8+ T cells. J Immunol. 2013;190:428–37. doi:10.4049/jimmunol.1201361.

    Article  CAS  PubMed  Google Scholar 

  164. Wang Y, et al. GATA-3 controls the maintenance and proliferation of T cells downstream of TCR and cytokine signaling. Nat Immunol. 2013;14:714–22. doi:10.1038/ni.2623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89:587–96.

    Article  CAS  PubMed  Google Scholar 

  166. Ouyang W, et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity. 1998;9:745–55.

    Article  CAS  PubMed  Google Scholar 

  167. Pai SY, Truitt ML, Ho IC. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci U S A. 2004;101:1993–8. doi:10.1073/pnas.0308697100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Lee HJ, et al. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med. 2000;192:105–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. 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. 1997;272:21597–603.

    Article  CAS  PubMed  Google Scholar 

  170. Kishikawa H, Sun J, Choi A, Miaw SC, Ho IC. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. J Immunol. 2001;167:4414–20.

    Article  CAS  PubMed  Google Scholar 

  171. Hosokawa H, et al. Methylation of gata3 protein at arg-261 regulates transactivation of the il5 gene in T helper 2 cells. J Biol Chem. 2015;290:13095–103. doi:10.1074/jbc.M114.621524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yagi R, Zhu J, Paul WE. An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation. Int Immunol. 2011;23:415–20. doi:10.1093/intimm/dxr029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wei G, et al. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity. 2011;35:299–311. doi:10.1016/j.immuni.2011.08.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Horiuchi S, et al. Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3. J Immunol. 2011;186:6378–89. doi:10.4049/jimmunol.1100179.

    Article  CAS  PubMed  Google Scholar 

  175. Kanhere A, et al. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Commun. 2012;3:1268. doi:10.1038/ncomms2260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Ho IC, Hodge MR, Rooney JW, Glimcher LH. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell. 1996;85:973–83.

    Article  CAS  PubMed  Google Scholar 

  177. Nurieva RI, et al. Transcriptional regulation of th2 differentiation by inducible costimulator. Immunity. 2003;18:801–11.

    Article  CAS  PubMed  Google Scholar 

  178. 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;10:167–75. doi:10.1038/ni.1690.

    Article  CAS  PubMed  Google Scholar 

  179. Hodge MR, et al. NF-AT-Driven interleukin-4 transcription potentiated by NIP45. Science. 1996;274:1903–5.

    Article  CAS  PubMed  Google Scholar 

  180. Fathman JW, et al. NIP45 controls the magnitude of the type 2 T helper cell response. Proc Natl Acad Sci U S A. 2010;107:3663–8. doi:10.1073/pnas.0914700107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Ho IC, Lo D, Glimcher LH. c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms. J Exp Med. 1998;188:1859–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Kim JI, Ho IC, Grusby MJ, Glimcher LH. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity. 1999;10:745–51.

    Article  CAS  PubMed  Google Scholar 

  183. Leavenworth JW, Ma X, Mo YY, Pauza ME. SUMO conjugation contributes to immune deviation in nonobese diabetic mice by suppressing c-Maf transactivation of IL-4. J Immunol. 2009;183:1110–9. doi:10.4049/jimmunol.0803671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Lin BS, et al. SUMOylation attenuates c-Maf-dependent IL-4 expression. Eur J Immunol. 2010;40:1174–84. doi:10.1002/eji.200939788.

    Article  CAS  PubMed  Google Scholar 

  185. Lai CY, et al. Tyrosine phosphorylation of c-Maf enhances the expression of IL-4 gene. J Immunol. 2012;189:1545–50. doi:10.4049/jimmunol.1200405.

    Article  CAS  PubMed  Google Scholar 

  186. Liu CC, et al. Reciprocal regulation of C-Maf tyrosine phosphorylation by Tec and Ptpn22. PLoS One. 2015;10:e0127617. doi:10.1371/journal.pone.0127617.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Rincon M, Derijard B, Chow CW, Davis RJ, Flavell RA. Reprogramming the signalling requirement for AP-1 (activator protein-1) activation during differentiation of precursor CD4+ T-cells into effector Th1 and Th2 cells. Genes Funct. 1997;1:51–68.

    Article  CAS  PubMed  Google Scholar 

  188. 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;18:420–32. doi:10.1093/emboj/18.2.420.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Hartenstein B, et al. Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB. EMBO J. 2002;21:6321–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Goplen N, et al. ERK1 is important for Th2 differentiation and development of experimental asthma. FASEB J: Off Publ Fed Am Soc Exp Biol. 2012;26:1934–45. doi:10.1096/fj.11-196477.

    Article  CAS  Google Scholar 

  191. Garaude J, et al. SUMOylation regulates the transcriptional activity of JunB in T lymphocytes. J Immunol. 2008;180:5983–90.

    Article  CAS  PubMed  Google Scholar 

  192. Fang D, et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol. 2002;3:281–7. doi:10.1038/ni763.

    Article  CAS  PubMed  Google Scholar 

  193. Oliver PM, et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity. 2006;25:929–40. doi:10.1016/j.immuni.2006.10.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Yang XO, et al. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol. 2009;10:1260–6. doi:10.1038/ni.1821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Liu Z, et al. Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling. J Immunol. 2009;183:6320–9. doi:10.4049/jimmunol.0900975.

    Article  CAS  PubMed  Google Scholar 

  196. Kwon SJ, et al. KLF13 cooperates with c-Maf to regulate IL-4 expression in CD4+ T cells. J Immunol. 2014;192:5703–9. doi:10.4049/jimmunol.1302830.

    Article  CAS  PubMed  Google Scholar 

  197. Guo J, et al. Yin-Yang 1 activates interleukin-4 gene expression in T cells. J Biol Chem. 2001;276:48871–8. doi:10.1074/jbc.M101592200.

    Article  CAS  PubMed  Google Scholar 

  198. Hwang SS, et al. Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation. Proc Natl Acad Sci U S A. 2013;110:276–81. doi:10.1073/pnas.1214682110.

    Article  CAS  PubMed  Google Scholar 

  199. Guo J, Lin X, Williams MA, Hamid Q, Georas SN. Yin-Yang 1 regulates effector cytokine gene expression and T(H)2 immune responses. J Allergy Clin Immunol.2008;122:195–201, 201 e191-195. doi:10.1016/j.jaci.2008.03.012.

    Google Scholar 

  200. Dickinson LA, Joh T, Kohwi Y, Kohwi-Shigematsu T. A tissue-specific MAR/SAR DNA-binding protein with unusual binding site recognition. Cell. 1992;70:631–45.

    Article  CAS  PubMed  Google Scholar 

  201. Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature. 2002;419:641–5. doi:10.1038/nature01084.

    Article  CAS  PubMed  Google Scholar 

  202. Ahlfors H, et al. SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation. Blood. 2010;116:1443–53. doi:10.1182/blood-2009-11-252205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Son JS, Chae CS, Hwang JS, Park ZY, Im SH. Enhanced chromatin accessibility and recruitment of JUNB mediate the sustained IL-4 expression in NFAT1 deficient T helper 2 cells. PLoS One. 2011;6:e22042. doi:10.1371/journal.pone.0022042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Elser B, et al. IFN-gamma represses IL-4 expression via IRF-1 and IRF-2. Immunity. 2002;17:703–12.

    Article  CAS  PubMed  Google Scholar 

  205. Maruyama S, et al. A novel function of interferon regulatory factor-1: inhibition of Th2 cells by down-regulating the Il4 gene during Listeria infection. Int Immunol. 2015;27:143–52. doi:10.1093/intimm/dxu092.

    Article  CAS  PubMed  Google Scholar 

  206. Naoe Y, et al. Repression of interleukin-4 in T helper type 1 cells by Runx/Cbf beta binding to the Il4 silencer. J Exp Med. 2007;204:1749–55. doi:10.1084/jem.20062456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Kohu K, et al. The Runx3 transcription factor augments Th1 and down-modulates Th2 phenotypes by interacting with and attenuating GATA3. J Immunol. 2009;183:7817–24. doi:10.4049/jimmunol.0802527.

    Article  CAS  PubMed  Google Scholar 

  208. Chang HC, et al. PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity. 2005;22:693–703. doi:10.1016/j.immuni.2005.03.016.

    Article  CAS  PubMed  Google Scholar 

  209. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997;276:589–92.

    Article  CAS  PubMed  Google Scholar 

  210. Kusam S, Toney LM, Sato H, Dent AL. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J Immunol. 2003;170:2435–41.

    Article  CAS  PubMed  Google Scholar 

  211. Kuwahara M, et al. The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-beta and suppresses T(H)2 differentiation. Nat Immunol. 2012;13:778–86. doi:10.1038/ni.2362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Lee DU, Agarwal S, Rao A. Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity. 2002;16:649–60.

    Article  CAS  PubMed  Google Scholar 

  213. Makar KW, et al. Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Nat Immunol. 2003;4:1183–90. doi:10.1038/ni1004.

    Article  CAS  PubMed  Google Scholar 

  214. Santangelo S, Cousins DJ, Winkelmann NE, Staynov DZ. DNA methylation changes at human Th2 cytokine genes coincide with DNase I hypersensitive site formation during CD4(+) T cell differentiation. J Immunol. 2002;169:1893–903.

    Article  CAS  PubMed  Google Scholar 

  215. Hutchins AS, et al. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002;10:81–91.

    Article  CAS  PubMed  Google Scholar 

  216. Kaneko T, et al. Chromatin remodeling at the Th2 cytokine gene loci in human type 2 helper T cells. Mol Immunol. 2007;44:2249–56. doi:10.1016/j.molimm.2006.11.004.

    Article  CAS  PubMed  Google Scholar 

  217. 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;30:155–67. doi:10.1016/j.immuni.2008.12.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Seumois G, et al. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. Nat Immunol. 2014;15:777–88. doi:10.1038/ni.2937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Gamper CJ, Agoston AT, Nelson WG, Powell JD. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009;183:2267–76. doi:10.4049/jimmunol.0802960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Yu Q, et al. DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. Proc Natl Acad Sci U S A. 2012;109:541–6. doi:10.1073/pnas.1103803109.

    Article  CAS  PubMed  Google Scholar 

  221. Thomas RM, Gamper CJ, Ladle BH, Powell JD, Wells AD. De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem. 2012;287:22900–9. doi:10.1074/jbc.M111.312785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Makar KW, Wilson CB. DNA methylation is a nonredundant repressor of the Th2 effector program. J Immunol. 2004;173:4402–6.

    Article  CAS  PubMed  Google Scholar 

  223. Koyanagi M, et al. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem. 2005;280:31470–7. doi:10.1074/jbc.M504766200.

    Article  CAS  PubMed  Google Scholar 

  224. Tumes DJ, et al. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity. 2013;39:819–32. doi:10.1016/j.immuni.2013.09.012.

    Article  CAS  PubMed  Google Scholar 

  225. Grausenburger R, et al. Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol. 2010;185:3489–97. doi:10.4049/jimmunol.0903610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Li Q, et al. Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun. 2014;5:5780. doi:10.1038/ncomms6780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Yamashita M, et al. Crucial role of MLL for the maintenance of memory T helper type 2 cell responses. Immunity. 2006;24:611–22. doi:10.1016/j.immuni.2006.03.017.

    Article  CAS  PubMed  Google Scholar 

  228. Nakata Y, et al. c-Myb, Menin, GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T helper type 2 cell development. Blood. 2010;116:1280–90. doi:10.1182/blood-2009-05-223255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Kimura M, et al. Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene. Immunity. 2001;15:275–87.

    Article  CAS  PubMed  Google Scholar 

  230. Lehnertz B, et al. Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J Exp Med. 2010;207:915–22. doi:10.1084/jem.20100363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Turner M, Galloway A, Vigorito E. Noncoding RNA and its associated proteins as regulatory elements of the immune system. Nat Immunol. 2014;15:484–91. doi:10.1038/ni.2887.

    Article  CAS  PubMed  Google Scholar 

  232. Lu TX, Munitz A, Rothenberg ME. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol. 2009;182:4994–5002. doi:10.4049/jimmunol.0803560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Lu TX, et al. MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol. 2012;129:1064–1075 e1069. doi:10.1016/j.jaci.2012.01.060.

    Google Scholar 

  234. Vennegaard MT, et al. Allergic contact dermatitis induces upregulation of identical microRNAs in humans and mice. Contact Dermatitis. 2012;67:298–305. doi:10.1111/j.1600-0536.2012.02083.x.

    Article  CAS  PubMed  Google Scholar 

  235. Sawant DV, Wu H, Kaplan MH, Dent AL. The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway. Mol Immunol. 2013;54:435–42. doi:10.1016/j.molimm.2013.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Chen RF, et al. MicroRNA-21 expression in neonatal blood associated with antenatal immunoglobulin E production and development of allergic rhinitis. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2010;40:1482–90. doi:10.1111/j.1365-2222.2010.03592.x.

    Article  CAS  Google Scholar 

  237. Thai TH, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604–8. doi:10.1126/science.1141229.

    Article  CAS  PubMed  Google Scholar 

  238. Rodriguez A, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608–11. doi:10.1126/science.1139253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Sonkoly E, et al. 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. 2010;126(581–589):e581–520. doi:10.1016/j.jaci.2010.05.045.

    Article  CAS  Google Scholar 

  240. Malmhall C, et al. MicroRNA-155 is essential for T(H)2-mediated allergen-induced eosinophilic inflammation in the lung. J Allergy Clin Immunol. 2014;133:1429–1438, 1438 e1421-1427. doi:10.1016/j.jaci.2013.11.008.

    Google Scholar 

  241. Simpson LJ, et al. A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production. Nat Immunol. 2014;15:1162–70. doi:10.1038/ni.3026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Ranzani V, et al. The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4. Nat Immunol. 2015;16:318–25. doi:10.1038/ni.3093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Spurlock 3rd CF, et al. Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat Commun. 2015;6:6932. doi:10.1038/ncomms7932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Yusuf I, et al. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol. 2010;185:190–202. doi:10.4049/jimmunol.0903505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med. 2012;209:243–50. doi:10.1084/jem.20111174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Nurieva RI, et al. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem. 2012;287:11234–9. doi:10.1074/jbc.M111.324046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Kroenke MA, et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol. 2012;188:3734–44. doi:10.4049/jimmunol.1103246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Sherman MA, Nachman TY, Brown MA. Cutting edge: IL-4 production by mast cells does not require c-maf. J Immunol. 1999;163:1733–6.

    CAS  PubMed  Google Scholar 

  249. Sherman MA, Secor VH, Lee SK, Lopez RD, Brown MA. STAT6-independent production of IL-4 by mast cells. Eur J Immunol. 1999;29:1235–42. doi:10.1002/(SICI)1521-4141(199904)29:04<1235::AID-IMMU1235>3.0.CO;2-0.

    Article  CAS  PubMed  Google Scholar 

  250. Gregory GD, Raju SS, Winandy S, Brown MA. Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. J Clin Invest. 2006;116:1327–36. doi:10.1172/JCI27227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Li Y, Qi X, Liu B, Huang H. The STAT5-GATA2 pathway is critical in basophil and mast cell differentiation and maintenance. J Immunol. 2015;194:4328–38. doi:10.4049/jimmunol.1500018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Nei Y, et al. GATA-1 regulates the generation and function of basophils. Proc Natl Acad Sci U S A. 2013;110:18620–5. doi:10.1073/pnas.1311668110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Li Y, Qi X, Liu B, Huang H. The STAT5-GATA2 pathway is critical in basophil and mast cell differentiation and maintenance. J Immunol. 2015. doi:10.4049/jimmunol.1500018.

    Google Scholar 

  254. Hural JA, Kwan M, Henkel G, Hock MB, Brown MA. An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells. J Immunol. 2000;165:3239–49.

    Article  CAS  PubMed  Google Scholar 

  255. Weiss DL, et al. Nuclear factor of activated T cells is associated with a mast cell interleukin 4 transcription complex. Mol Cell Biol. 1996;16:228–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Qi X, Nishida J, Chaves L, Ohmori K, Huang H. CCAAT/enhancer-binding protein alpha (C/EBPalpha) is critical for interleukin-4 expression in response to FcepsilonRI receptor cross-linking. J Biol Chem. 2011;286:16063–73. doi:10.1074/jbc.M110.213389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Ugajin T, et al. Zinc-binding metallothioneins are key modulators of IL-4 production by basophils. Mol Immunol. 2015;66:180–8. doi:10.1016/j.molimm.2015.03.002.

    Article  CAS  PubMed  Google Scholar 

  258. Weidinger S, Baurecht H, Naumann A, Novak N. Genome-wide association studies on IgE regulation: are genetics of IgE also genetics of atopic disease? Curr Opin Allergy Clin Immunol. 2010;10:408–17. doi:10.1097/ACI.0b013e32833d7d2d.

    Article  CAS  PubMed  Google Scholar 

  259. Martinez FD, Vercelli D. Asthma. Lancet. 2013;382:1360–72. doi:10.1016/S0140-6736(13)61536-6.

    Article  PubMed  Google Scholar 

  260. Moffatt MF, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363:1211–21. doi:10.1056/NEJMoa0906312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Li X, et al. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol. 2010;125:328–335 e311. doi:10.1016/j.jaci.2009.11.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Walker C, et al. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992;146:109–15. doi:10.1164/ajrccm/146.1.109.

    Article  CAS  PubMed  Google Scholar 

  263. Robinson DS, et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326:298–304. doi:10.1056/NEJM199201303260504.

    Article  CAS  PubMed  Google Scholar 

  264. Schieck M, et al. A polymorphism in the TH 2 locus control region is associated with changes in DNA methylation and gene expression. Allergy. 2014;69:1171–80. doi:10.1111/all.12450.

    Article  CAS  PubMed  Google Scholar 

  265. Stefanowicz D, et al. DNA methylation profiles of airway epithelial cells and PBMCs from healthy, atopic and asthmatic children. PLoS One. 2012;7:e44213. doi:10.1371/journal.pone.0044213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Begin P, Nadeau KC. Epigenetic regulation of asthma and allergic disease. Allergy Asthma Clin Immunol: Off J Can Soc Allergy Clin Immunol. 2014;10:27. doi:10.1186/1710-1492-10-27.

    Article  CAS  Google Scholar 

  267. Liang L, et al. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature. 2015;520:670–4. doi:10.1038/nature14125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Yang IV, et al. DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol. 2015;136:69–80. doi:10.1016/j.jaci.2015.01.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Hirota T, et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet. 2011;43:893–6. doi:10.1038/ng.887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Torgerson DG, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet. 2011;43:887–92. doi:10.1038/ng.888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Gudbjartsson DF, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009;41:342–7. doi:10.1038/ng.323.

    Article  CAS  PubMed  Google Scholar 

  272. Ying S, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005;174:8183–90.

    Article  CAS  PubMed  Google Scholar 

  273. Ying S, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008;181:2790–8.

    Article  CAS  PubMed  Google Scholar 

  274. Prefontaine D, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009;183:5094–103. doi:10.4049/jimmunol.0802387.

    Article  CAS  PubMed  Google Scholar 

  275. Kurowska-Stolarska M, et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol. 2009;183:6469–77. doi:10.4049/jimmunol.0901575.

    Article  CAS  PubMed  Google Scholar 

  276. Corrigan CJ, et al. Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses. J Allergy Clin Immunol. 2011;128:116–24. doi:10.1016/j.jaci.2011.03.043.

    Article  CAS  PubMed  Google Scholar 

  277. Cheng D, et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am J Respir Crit Care Med. 2014;190:639–48. doi:10.1164/rccm.201403-0505OC.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  278. Beale J, et al. Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. Sci Transl Med. 2014;6:256ra134. doi:10.1126/scitranslmed.3009124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  279. Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med. 2015;21:698–708. doi:10.1038/nm.3892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Kabata H, Moro K, Koyasu S, Asano K. Group 2 innate lymphoid cells and asthma. Allergol Int: Off J Jpn Soc Allergol. 2015;64:227–34. doi:10.1016/j.alit.2015.03.004.

    Article  CAS  Google Scholar 

  281. Allakhverdi Z, et al. CD34+ hematopoietic progenitor cells are potent effectors of allergic inflammation. J Allergy Clin Immunol. 2009;123:472–8. doi:10.1016/j.jaci.2008.10.022.

    Article  CAS  PubMed  Google Scholar 

  282. Christianson CA, et al. Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J Allergy Clin Immunol. 2015. doi:10.1016/j.jaci.2014.11.037.

    PubMed  PubMed Central  Google Scholar 

  283. Xue L, et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol. 2014;133:1184–94. doi:10.1016/j.jaci.2013.10.056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Mjosberg J, et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity. 2012;37:649–59. doi:10.1016/j.immuni.2012.08.015.

    Article  PubMed  CAS  Google Scholar 

  285. Doherty TA, et al. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J Allergy Clin Immunol. 2013;132:205–13. doi:10.1016/j.jaci.2013.03.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Endo Y, et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity. 2015;42:294–308. doi:10.1016/j.immuni.2015.01.016.

    Article  CAS  PubMed  Google Scholar 

  287. Guo L, et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci U S A. 2009;106:13463–8. doi:10.1073/pnas.0906988106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Omori M, Ziegler S. Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J Immunol. 2007;178:1396–404.

    Article  CAS  PubMed  Google Scholar 

  289. Angkasekwinai P, et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med. 2007;204:1509–17. doi:10.1084/jem.20061675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Rochman I, Watanabe N, Arima K, Liu YJ, Leonard WJ. Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells. J Immunol. 2007;178:6720–4.

    Article  CAS  PubMed  Google Scholar 

  291. Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011;41:1862–71. doi:10.1002/eji.201041195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Min B, et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med. 2004;200:507–17. doi:10.1084/jem.20040590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Oeser K, Schwartz C, Voehringer D. Conditional IL-4/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths. Mucosal Immunol. 2015;8:672–82. doi:10.1038/mi.2014.101.

    Article  CAS  PubMed  Google Scholar 

  294. Sullivan BM, et al. Genetic analysis of basophil function in vivo. Nat Immunol. 2011;12:527–35. doi:10.1038/ni.2036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Schwartz C, et al. Basophil-mediated protection against gastrointestinal helminths requires IgE-induced cytokine secretion. Proc Natl Acad Sci U S A. 2014;111:E5169–77. doi:10.1073/pnas.1412663111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008;9:310–8. doi:10.1038/ni1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Rosenstein RK, Bezbradica JS, Yu S, Medzhitov R. Signaling pathways activated by a protease allergen in basophils. Proc Natl Acad Sci U S A. 2014;111:E4963–71. doi:10.1073/pnas.1418959111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Phillips C, Coward WR, Pritchard DI, Hewitt CR. Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites. J Leukoc Biol. 2003;73:165–71.

    Article  CAS  PubMed  Google Scholar 

  299. Egawa M, et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. Immunity. 2013;38:570–80. doi:10.1016/j.immuni.2012.11.014.

    Article  CAS  PubMed  Google Scholar 

  300. Siracusa MC, et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature. 2011;477:229–33. doi:10.1038/nature10329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Glatman Zaretsky A, et al. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med. 2009;206:991–9. doi:10.1084/jem.20090303.

    Article  PubMed  CAS  Google Scholar 

  302. 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;206:1001–7. doi:10.1084/jem.20090313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Thomas SY, Chyung YH, Luster AD. Natural killer T cells are not the predominant T cell in asthma and likely modulate, not cause, asthma. J Allergy Clin Immunol. 2010;125:980–4. doi:10.1016/j.jaci.2010.01.032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Koyama K. NK1.1+ cell depletion in vivo fails to prevent protection against infection with the murine nematode parasite Trichuris muris. Parasite Immunol. 2002;24:527–33.

    Article  CAS  PubMed  Google Scholar 

  305. Mallevaey T, et al. Invariant and noninvariant natural killer T cells exert opposite regulatory functions on the immune response during murine schistosomiasis. Infect Immun. 2007;75:2171–80. doi:10.1128/IAI.01178-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Albacker LA, et al. Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity. Nat Med. 2013;19:1297–304. doi:10.1038/nm.3321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Travers J, Rothenberg ME. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015;8:464–75. doi:10.1038/mi.2015.2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. Chu DK, et al. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo. J Exp Med. 2014;211:1657–72. doi:10.1084/jem.20131800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Jacobsen EA, et al. Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice. Allergy. 2015. doi:10.1111/all.12655.

    PubMed  PubMed Central  Google Scholar 

  310. Borish LC, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001;107:963–70. doi:10.1067/mai.2001.115624.

    Article  CAS  PubMed  Google Scholar 

  311. Hart TK, et al. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol. 2002;130:93–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  312. Wenzel S, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455–66. doi:10.1056/NEJMoa1304048.

    Article  CAS  PubMed  Google Scholar 

  313. Beck LA, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9. doi:10.1056/NEJMoa1314768.

    Article  PubMed  CAS  Google Scholar 

  314. Krug N, et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 2015;372:1987–95. doi:10.1056/NEJMoa1411776.

    Article  PubMed  Google Scholar 

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  1. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    I-Cheng Ho

  2. College of Medicine, National Taiwan University, Taipei, Taiwan

    Shi-Chuen Miaw

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  1. State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China

    Xiaojing Ma

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Ho, IC., Miaw, SC. (2016). Regulation of IL-4 Expression in Immunity and Diseases. In: Ma, X. (eds) Regulation of Cytokine Gene Expression in Immunity and Diseases. Advances in Experimental Medicine and Biology, vol 941. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-0921-5_3

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