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Abstract

Helper T (Th) cell subsets direct immune responses by producing signature cytokines. Th2 cells produce IL-4, IL-5, and IL-13, which are important in humoral immunity and protection from helminth infection and are central to the pathogenesis of many allergic inflammatory diseases. Molecular analysis of Th2 cell differentiation and maintenance of function has led to recent discoveries that have refined our understanding of Th2 cell biology. Epigenetic regulation of expression by chromatin remodeling complexes such as Polycomb and Trithorax is crucial for maintaining Th2 cell identity. In the context of allergic diseases, memory-type pathogenic Th2 cells have been identified in both mice and humans. To better understand these disease-driving cell populations, we have developed a model called the pathogenic Th population disease induction model. The concept of defined subsets of pathogenic Th cells may spur new, effective strategies for treating intractable chronic inflammatory disorders.

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2017-04-26
2024-03-28
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Literature Cited

  1. Tada T. 1.  1997. The immune system as a supersystem. Annu. Rev. Immunol. 15:1–13 [Google Scholar]
  2. Mowen KA, Glimcher LH. 2.  2004. Signaling pathways in Th2 development. Immunol. Rev. 202:203–22 [Google Scholar]
  3. Paul WE, Zhu J. 3.  2010. How are TH2-type immune responses initiated and amplified?. Nat. Rev. Immunol. 10:225–35 [Google Scholar]
  4. Reiner SL. 4.  2007. Development in motion: helper T cells at work. Cell 129:33–36 [Google Scholar]
  5. Nakayama T, Yamashita M. 5.  2008. Initiation and maintenance of Th2 cell identity. Curr. Opin. Immunol. 20:265–71 [Google Scholar]
  6. Locksley RM. 6.  2009. Nine lives: plasticity among T helper cell subsets. J. Exp. Med. 206:1643–46 [Google Scholar]
  7. O'Shea JJ, Paul WE. 7.  2010. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–102 [Google Scholar]
  8. Ansel KM, Djuretic I, Tanasa B, Rao A. 8.  2006. Regulation of Th2 differentiation and Il4 locus accessibility. Annu. Rev. Immunol. 24:607–56 [Google Scholar]
  9. Wilson CB, Rowell E, Sekimata M. 9.  2009. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9:91–105 [Google Scholar]
  10. Umetsu DT, DeKruyff RH. 10.  2006. The regulation of allergy and asthma. Immunol. Rev. 212:238–55 [Google Scholar]
  11. Licona-Limon P, Kim LK, Palm NW, Flavell RA. 11.  2013. TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol. 14:536–42 [Google Scholar]
  12. Patel DD, Kuchroo VK. 12.  2015. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity 43:1040–51 [Google Scholar]
  13. Nakayama T, Yamashita M. 13.  2010. The TCR-mediated signaling pathways that control the direction of helper T cell differentiation. Semin. Immunol. 22:303–9 [Google Scholar]
  14. Chen L, Flies DB. 14.  2013. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13:227–42 [Google Scholar]
  15. Krummel MF, Bartumeus F, Gerard A. 15.  2016. T cell migration, search strategies and mechanisms. Nat. Rev. Immunol. 16:193–201 [Google Scholar]
  16. O'Shea JJ, Holland SM, Staudt LM. 16.  2013. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 368:161–70 [Google Scholar]
  17. Zheng W, Flavell RA. 17.  1997. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–96 [Google Scholar]
  18. Ho IC, Tai TS, Pai SY. 18.  2009. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat. Rev. Immunol. 9:125–35 [Google Scholar]
  19. Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V. 19.  et al. 2012. STATs shape the active enhancer landscape of T cell populations. Cell 151:981–93 [Google Scholar]
  20. Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME. 20.  et al. 2005. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6:1047–53 [Google Scholar]
  21. Fort MM, Cheung J, Yen D, Li J, Zurawski SM. 21.  et al. 2001. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–95 [Google Scholar]
  22. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E. 22.  et al. 2005. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–90 [Google Scholar]
  23. Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. 23.  1990. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med. 172:921–29 [Google Scholar]
  24. Endo Y, Hirahara K, Iinuma T, Shinoda K, Tumes DJ. 24.  et al. 2015. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42:294–308 [Google Scholar]
  25. Tindemans I, Serafini N, Di Santo JP, Hendriks RW. 25.  2014. GATA-3 function in innate and adaptive immunity. Immunity 41:191–206 [Google Scholar]
  26. Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P. 26.  et al. 2000. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406:419–22 [Google Scholar]
  27. Yui MA, Rothenberg EV. 27.  2014. Developmental gene networks: a triathlon on the course to T cell identity. Nat. Rev. Immunol. 14:529–45 [Google Scholar]
  28. Yamashita M, Ukai-Tadenuma M, Kimura M, Omori M, Inami M. 28.  et al. 2002. Identification of a conserved GATA3 response element upstream proximal from the interleukin-13 gene locus. J. Biol. Chem. 277:42399–408 [Google Scholar]
  29. Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A. 29.  et al. 2004. Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses. Nat. Immunol. 5:1157–65 [Google Scholar]
  30. Pai SY, Truitt ML, Ho IC. 30.  2004. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. PNAS 101:1993–98 [Google Scholar]
  31. Zhang DH, Yang L, Ray A. 31.  1998. Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3. J. Immunol. 161:3817–21 [Google Scholar]
  32. Constant S, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K. 32.  1995. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J. Exp. Med. 182:1591–96 [Google Scholar]
  33. Hosken NA, Shibuya K, Heath AW, Murphy KM, O'Garra A. 33.  1995. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor–αβ–transgenic model. J. Exp. Med. 182:1579–84 [Google Scholar]
  34. Yamane H, Zhu J, Paul WE. 34.  2005. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. J. Exp. Med. 202:793–804 [Google Scholar]
  35. van Panhuys N. 35.  2016. TCR Signal strength alters T-DC activation and interaction times and directs the outcome of differentiation. Front. Immunol. 7:6 [Google Scholar]
  36. Yamashita M, Kimura M, Kubo M, Shimizu C, Tada T. 36.  et al. 1999. T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation. PNAS 96:1024–29 [Google Scholar]
  37. Balamuth F, Leitenberg D, Unternaehrer J, Mellman I, Bottomly K. 37.  2001. Distinct patterns of membrane microdomain partitioning in Th1 and Th2 cells. Immunity 15:729–38 [Google Scholar]
  38. Itoh Y, Wang Z, Ishida H, Eichelberg K, Fujimoto N. 38.  et al. 2005. Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling. Eur. J. Immunol. 35:3187–95 [Google Scholar]
  39. Tubo NJ, Jenkins MK. 39.  2014. TCR signal quantity and quality in CD4 T cell differentiation. Trends Immunol 35:591–96 [Google Scholar]
  40. Tubo NJ, Pagan AJ, Taylor JJ, Nelson RW, Linehan JL. 40.  et al. 2013. Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153:785–96 [Google Scholar]
  41. Fazilleau N, McHeyzer-Williams LJ, Rosen H, McHeyzer-Williams MG. 41.  2009. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat. Immunol. 10:375–84 [Google Scholar]
  42. Shibata Y, Kamata T, Kimura M, Yamashita M, Wang CR. 42.  et al. 2002. Ras activation in T cells determines the development of antigen-induced airway hyperresponsiveness and eosinophilic inflammation. J. Immunol. 169:2134–40 [Google Scholar]
  43. Goplen N, Karim Z, Guo L, Zhuang Y, Huang H. 43.  et al. 2012. ERK1 is important for Th2 differentiation and development of experimental asthma. FASEB J 26:1934–45 [Google Scholar]
  44. Yamashita M, Shinnakasu R, Asou H, Kimura M, Hasegawa A. 44.  et al. 2005. Ras-ERK MAPK cascade regulates GATA3 stability and Th2 differentiation through ubiquitin-proteasome pathway. J. Biol. Chem. 280:29409–19 [Google Scholar]
  45. Shinnakasu R, Yamashita M, Kuwahara M, Hosokawa H, Hasegawa A. 45.  et al. 2008. Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation. J. Biol. Chem. 283:28216–25 [Google Scholar]
  46. Dong C, Yang DD, Wysk M, Whitmarsh AJ, Davis RJ, Flavell RA. 46.  1998. Defective T cell differentiation in the absence of Jnk1. Science 282:2092–95 [Google Scholar]
  47. Rincon M, Enslen H, Raingeaud J, Recht M, Zapton T. 47.  et al. 1998. Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J 17:2817–29 [Google Scholar]
  48. Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C. 48.  et al. 2000. T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex. J. Exp. Med. 191:1869–79 [Google Scholar]
  49. Kiani A, Rao A, Aramburu J. 49.  2000. Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity 12:359–72 [Google Scholar]
  50. Marsland BJ, Soos TJ, Spath G, Littman DR, Kopf M. 50.  2004. Protein kinase C θ is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. J. Exp. Med. 200:181–89 [Google Scholar]
  51. Balasubramani A, Shibata Y, Crawford GE, Baldwin AS, Hatton RD, Weaver CT. 51.  2010. Modular utilization of distal cis-regulatory elements controls. Ifng gene expression in T cells activated by distinct stimuli. Immunity 33:35–47 [Google Scholar]
  52. Tan SL, Zhao J, Bi C, Chen XC, Hepburn DL. 52.  et al. 2006. Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase Cθ-deficient mice. J. Immunol. 176:2872–79 [Google Scholar]
  53. Yang B, Gay DL, MacLeod MK, Cao X, Hala T. 53.  et al. 2008. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nat. Immunol. 9:1356–63 [Google Scholar]
  54. O'Leary CE, Riling CR, Spruce LA, Ding H, Kumar S. 54.  et al. 2016. Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells. Nat. Commun. 7:11226 [Google Scholar]
  55. Mondino A, Mueller DL. 55.  2007. mTOR at the crossroads of T cell proliferation and tolerance. Semin. Immunol. 19:162–72 [Google Scholar]
  56. Pollizzi KN, Powell JD. 56.  2014. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14:435–46 [Google Scholar]
  57. Chi H. 57.  2012. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12:325–38 [Google Scholar]
  58. Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G. 58.  et al. 2013. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39:1043–56 [Google Scholar]
  59. Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S. 59.  et al. 2010. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:743–53 [Google Scholar]
  60. Heikamp EB, Patel CH, Collins S, Waickman A, Oh MH. 60.  et al. 2014. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat. Immunol. 15:457–64 [Google Scholar]
  61. Holmberg J, Perlmann T. 61.  2012. Maintaining differentiated cellular identity. Nat. Rev. Genet. 13:429–39 [Google Scholar]
  62. Greer EL, Shi Y. 62.  2012. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13:343–57 [Google Scholar]
  63. Nakayama T, Yamashita M. 63.  2009. Critical role of the Polycomb and Trithorax complexes in the maintenance of CD4 T cell memory. Semin. Immunol. 21:78–83 [Google Scholar]
  64. Onodera A, Nakayama T. 64.  2015. Epigenetics of T cells regulated by Polycomb/Trithorax molecules. Trends Mol. Med. 21:330–40 [Google Scholar]
  65. Di Croce L, Helin K. 65.  2013. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20:1147–55 [Google Scholar]
  66. Mohan M, Herz HM, Shilatifard A. 66.  2012. SnapShot: histone lysine methylase complexes. Cell 149:498 [Google Scholar]
  67. Steffen PA, Ringrose L. 67.  2014. What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. Nat. Rev. Mol. Cell Biol. 15:340–56 [Google Scholar]
  68. Hopkin AS, Gordon W, Klein RH, Espitia F, Daily K. 68.  et al. 2012. GRHL3/GET1 and Trithorax group members collaborate to activate the epidermal progenitor differentiation program. PLOS Genet 8:e1002829 [Google Scholar]
  69. Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P. 69.  et al. 2004. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431:873–78 [Google Scholar]
  70. Schuettengruber B, Martinez AM, Iovino N, Cavalli G. 70.  2011. Trithorax group proteins: switching genes on and keeping them active. Nat. Rev. Mol. Cell Biol. 12:799–814 [Google Scholar]
  71. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ. 71.  et al. 2006. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–26 [Google Scholar]
  72. Onodera A, Tumes DJ, Watanabe Y, Hirahara K, Kaneda A. 72.  et al. 2015. Spatial interplay between Polycomb and Trithorax complexes controls transcriptional activity in T lymphocytes. Mol. Cell. Biol. 35:3841–53 [Google Scholar]
  73. Onodera A, Yamashita M, Endo Y, Kuwahara M, Tofukuji S. 73.  et al. 2010. STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells. J. Exp. Med. 207:2493–506 [Google Scholar]
  74. Scheinman EJ, Avni O. 74.  2009. 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. 284:3037–48 [Google Scholar]
  75. Wei L, Vahedi G, Sun HW, Watford WT, Takatori H. 75.  et al. 2010. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32:840–51 [Google Scholar]
  76. Horiuchi S, Onodera A, Hosokawa H, Watanabe Y, Tanaka T. 76.  et al. 2011. Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3. J. Immunol. 186:6378–89 [Google Scholar]
  77. Ouyang W, Lohning M, Gao Z, Assenmacher M, Ranganath S. 77.  et al. 2000. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12:27–37 [Google Scholar]
  78. Elo LL, Jarvenpaa H, Tuomela S, Raghav S, Ahlfors H. 78.  et al. 2010. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity 32:852–62 [Google Scholar]
  79. Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y. 79.  et al. 2013. The Polycomb protein Ezh2 regulates differentiation and plasticity of CD4+ T helper type 1 and type 2 cells. Immunity 39:819–32 [Google Scholar]
  80. Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, Bix M. 80.  2005. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J. Biol. Chem. 280:31470–77 [Google Scholar]
  81. Allan RS, Zueva E, Cammas F, Schreiber HA, Masson V. 81.  et al. 2012. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 487:249–53 [Google Scholar]
  82. Kimura M, Koseki Y, Yamashita M, Watanabe N, Shimizu C. 82.  et al. 2001. Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene. Immunity 15:275–87 [Google Scholar]
  83. Hosokawa H, Kimura MY, Shinnakasu R, Suzuki A, Miki T. 83.  et al. 2006. Regulation of Th2 cell development by Polycomb group gene bmi-1 through the stabilization of GATA3. J. Immunol. 177:7656–64 [Google Scholar]
  84. Suzuki A, Iwamura C, Shinoda K, Tumes DJ, Kimura MY. 84.  et al. 2010. Polycomb group gene product Ring1B regulates Th2-driven airway inflammation through the inhibition of Bim-mediated apoptosis of effector Th2 cells in the lung. J. Immunol. 184:4510–20 [Google Scholar]
  85. Park IK, Qian D, Kiel M, Becker MW, Pihalja M. 85.  et al. 2003. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–5 [Google Scholar]
  86. Liu J, Cao L, Chen J, Song S, Lee IH. 86.  et al. 2009. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459:387–92 [Google Scholar]
  87. Gil J, O'Loghlen A. 87.  2014. PRC1 complex diversity: Where is it taking us?. Trends Cell Biol 24:632–41 [Google Scholar]
  88. Yamashita M, Hirahara K, Shinnakasu R, Hosokawa H, Norikane S. 88.  et al. 2006. Crucial role of MLL for the maintenance of memory T helper type 2 cell responses. Immunity 24:611–22 [Google Scholar]
  89. Nakata Y, Brignier AC, Jin S, Shen Y, Rudnick SI. 89.  et al. 2010. 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 116:1280–90 [Google Scholar]
  90. Zediak VP, Wherry EJ, Berger SL. 90.  2011. The contribution of epigenetic memory to immunologic memory. Curr. Opin. Genet. Dev. 21:154–59 [Google Scholar]
  91. Yamashita M, Kuwahara M, Suzuki A, Hirahara K, Shinnaksu R. 91.  et al. 2008. Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene. J. Exp. Med. 205:1109–20 [Google Scholar]
  92. Yamashita M, Ukai-Tadenuma M, Miyamoto T, Sugaya K, Hosokawa H. 92.  et al. 2004. Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci. J. Biol. Chem. 279:26983–90 [Google Scholar]
  93. Sasaki T, Onodera A, Hosokawa H, Watanabe Y, Horiuchi S. 93.  et al. 2013. Genome-wide gene expression profiling revealed a critical role for GATA3 in the maintenance of the Th2 cell identity. PLOS ONE 8:e66468 [Google Scholar]
  94. Islam SA, Chang DS, Colvin RA, Byrne MH, McCully ML. 94.  et al. 2011. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ TH2 cells. Nat. Immunol. 12:167–77 [Google Scholar]
  95. Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y. 95.  et al. 2010. The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 32:670–80 [Google Scholar]
  96. Sahoo A, Alekseev A, Obertas L, Nurieva R. 96.  2014. Grail controls Th2 cell development by targeting STAT6 for degradation. Nat. Commun. 5:4732 [Google Scholar]
  97. Polte T, Behrendt AK, Hansen G. 97.  2006. Direct evidence for a critical role of CD30 in the development of allergic asthma. J. Allergy Clin. Immunol. 118:942–48 [Google Scholar]
  98. Takemoto N, Arai K, Miyatake S. 98.  2002. Cutting edge: the differential involvement of the N-finger of GATA-3 in chromatin remodeling and transactivation during Th2 development. J. Immunol. 169:4103–7 [Google Scholar]
  99. Hosokawa H, Tanaka T, Endo Y, Kato M, Shinoda K. 99.  et al. 2016. Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells. Nat. Commun. 7:11289 [Google Scholar]
  100. Zhang DH, Yang L, Cohn L, Parkyn L, Homer R. 100.  et al. 1999. Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. Immunity 11:473–82 [Google Scholar]
  101. Shinnakasu R, Yamashita M, Shinoda K, Endo Y, Hosokawa H. 101.  et al. 2006. Critical YxKxHxxxRP motif in the C-terminal region of GATA3 for its DNA binding and function. J. Immunol. 177:5801–10 [Google Scholar]
  102. Wang J, Shannon MF, Young IG. 102.  2006. A role for Ets1, synergizing with AP-1 and GATA-3 in the regulation of IL-5 transcription in mouse Th2 lymphocytes. Int. Immunol. 18:313–23 [Google Scholar]
  103. Hwang SS, Kim YU, Lee S, Jang SW, Kim MK. 103.  et al. 2013. Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation. PNAS 110:276–81 [Google Scholar]
  104. Chang HC, Zhang S, Thieu VT, Slee RB, Bruns HA. 104.  et al. 2005. PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity 22:693–703 [Google Scholar]
  105. Endo Y, Iwamura C, Kuwahara M, Suzuki A, Sugaya K. 105.  et al. 2011. Eomesodermin controls interleukin-5 production in memory T helper 2 cells through inhibition of activity of the transcription factor GATA3. Immunity 35:733–45 [Google Scholar]
  106. Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH. 106.  2005. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307:430–33 [Google Scholar]
  107. Kurata H, Lee HJ, McClanahan T, Coffman RL, O'Garra A, Arai N. 107.  2002. Friend of GATA is expressed in naive Th cells and functions as a repressor of GATA-3-mediated Th2 cell development. J. Immunol. 168:4538–45 [Google Scholar]
  108. Kuwahara M, Yamashita M, Shinoda K, Tofukuji S, Onodera A. 108.  et al. 2012. The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-beta and suppresses TH2 differentiation. Nat. Immunol. 13:778–86 [Google Scholar]
  109. Miaw SC, Choi A, Yu E, Kishikawa H, Ho IC. 109.  2000. ROG, repressor of GATA, regulates the expression of cytokine genes. Immunity 12:323–33 [Google Scholar]
  110. Hosokawa H, Tanaka T, Kato M, Shinoda K, Tohyama H. 110.  et al. 2013. Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression. PNAS 110:18626–31 [Google Scholar]
  111. Hosokawa H, Kato M, Tohyama H, Tamaki Y, Endo Y. 111.  et al. 2015. Methylation of Gata3 protein at Arg-261 regulates transactivation of the Il5 gene in T helper 2 cells. J. Biol. Chem. 290:13095–103 [Google Scholar]
  112. Wei G, Abraham BJ, Yagi R, Jothi R, Cui K. 112.  et al. 2011. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35:299–311 [Google Scholar]
  113. Hosokawa H, Tanaka T, Suzuki Y, Iwamura C, Ohkubo S. 113.  et al. 2013. Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity. PNAS 110:4691–96 [Google Scholar]
  114. Stein J, Maxeiner JH, Montermann E, Hohn Y, Raker V. 114.  et al. 2014. Non-eosinophilic airway hyper-reactivity in mice, induced by IFN-gamma producing CD4+ and CD8+ lung T cells, is responsive to steroid treatment. Scand. J. Immunol. 80:327–38 [Google Scholar]
  115. Huen J, Kakihara Y, Ugwu F, Cheung KL, Ortega J, Houry WA. 115.  2010. Rvb1-Rvb2: essential ATP-dependent helicases for critical complexes. Biochem. Cell Biol. 88:29–40 [Google Scholar]
  116. Endo Y, Hirahara K, Yagi R, Tumes DJ, Nakayama T. 116.  2014. Pathogenic memory type Th2 cells in allergic inflammation. Trends Immunol 35:69–78 [Google Scholar]
  117. Sallusto F, Lanzavecchia A. 117.  2009. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur. J. Immunol. 39:2076–82 [Google Scholar]
  118. Wang YH, Voo KS, Liu B, Chen CY, Uygungil B. 118.  et al. 2010. A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J. Exp. Med. 207:2479–91 [Google Scholar]
  119. Hegazy AN, Peine M, Helmstetter C, Panse I, Frohlich A. 119.  et al. 2010. Interferons direct Th2 cell reprogramming to generate a stable GATA-3+T-bet+ cell subset with combined Th2 and Th1 cell functions. Immunity 32:116–28 [Google Scholar]
  120. Upadhyaya B, Yin Y, Hill BJ, Douek DC, Prussin C. 120.  2011. Hierarchical IL-5 expression defines a subpopulation of highly differentiated human Th2 cells. J. Immunol. 187:3111–20 [Google Scholar]
  121. Wilke CM, Bishop K, Fox D, Zou W. 121.  2011. Deciphering the role of Th17 cells in human disease. Trends Immunol 32:603–11 [Google Scholar]
  122. Raymond M, Van VQ, Wakahara K, Rubio M, Sarfati M. 122.  2011. Lung dendritic cells induce TH17 cells that produce TH2 cytokines, express GATA-3, and promote airway inflammation. J. Allergy Clin. Immunol. 128:192–201.e6 [Google Scholar]
  123. Cosmi L, Maggi L, Santarlasci V, Capone M, Cardilicchia E. 123.  et al. 2010. Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4. J. Allergy Clin. Immunol. 125:222–30.e4 [Google Scholar]
  124. Carbone FR, Mackay LK, Heath WR, Gebhardt T. 124.  2013. Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. Curr. Opin. Immunol. 25:329–33 [Google Scholar]
  125. Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT. 125.  et al. 2005. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6:1236–44 [Google Scholar]
  126. Saenz SA, Noti M, Artis D. 126.  2010. Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol 31:407–13 [Google Scholar]
  127. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M. 127.  et al. 2010. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464:1367–70 [Google Scholar]
  128. Halim TY, Krauss RH, Sun AC, Takei F. 128.  2012. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36:451–63 [Google Scholar]
  129. Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J. 129.  et al. 2013. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat. Commun. 4:2675 [Google Scholar]
  130. Halim TY, Hwang YY, Scanlon ST, Zaghouani H, Garbi N. 130.  et al. 2016. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat. Immunol. 17:57–64 [Google Scholar]
  131. Shih HY, Sciume G, Mikami Y, Guo L, Sun HW. 131.  et al. 2016. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell 165:1120–33 [Google Scholar]
  132. Molofsky AB, Savage AK, Locksley RM. 132.  2015. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42:1005–19 [Google Scholar]
  133. Lloyd CM. 133.  2010. IL-33 family members and asthma—bridging innate and adaptive immune responses. Curr. Opin. Immunol. 22:800–6 [Google Scholar]
  134. Odegaard JI, Lee MW, Sogawa Y, Bertholet AM, Locksley RM. 134.  et al. 2016. Perinatal licensing of thermogenesis by IL-33 and ST2. Cell 166:841–54 [Google Scholar]
  135. Grotenboer NS, Ketelaar ME, Koppelman GH, Nawijn MC. 135.  2013. Decoding asthma: translating genetic variation in IL33 and IL1RL1 into disease pathophysiology. J. Allergy Clin. Immunol. 131:856–65 [Google Scholar]
  136. Ziegler SF. 136.  2010. The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr. Opin. Immunol. 22:795–99 [Google Scholar]
  137. Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K. 137.  et al. 2007. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204:1837–47 [Google Scholar]
  138. Walker JA, Barlow JL, McKenzie AN. 138.  2013. Innate lymphoid cells—how did we miss them?. Nat. Rev. Immunol. 13:75–87 [Google Scholar]
  139. Liu X, Li M, Wu Y, Zhou Y, Zeng L, Huang T. 139.  2009. Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma. Biochem. Biophys. Res. Commun. 386:181–85 [Google Scholar]
  140. Coyle AJ, Lloyd C, Tian J, Nguyen T, Erikkson C. 140.  et al. 1999. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J. Exp. Med. 190:895–902 [Google Scholar]
  141. Kurowska-Stolarska M, Kewin P, Murphy G, Russo RC, Stolarski B. 141.  et al. 2008. IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J. Immunol. 181:4780–90 [Google Scholar]
  142. Oboki K, Ohno T, Kajiwara N, Arae K, Morita H. 142.  et al. 2010. IL-33 is a crucial amplifier of innate rather than acquired immunity. PNAS 107:18581–86 [Google Scholar]
  143. Hoshino K, Kashiwamura S, Kuribayashi K, Kodama T, Tsujimura T. 143.  et al. 1999. The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function. J. Exp. Med. 190:1541–48 [Google Scholar]
  144. van Leeuwen EM, Sprent J, Surh CD. 144.  2009. Generation and maintenance of memory CD4+ T Cells. Curr. Opin. Immunol. 21:167–72 [Google Scholar]
  145. Lenz DC, Kurz SK, Lemmens E, Schoenberger SP, Sprent J. 145.  et al. 2004. IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory. PNAS 101:9357–62 [Google Scholar]
  146. Purton JF, Tan JT, Rubinstein MP, Kim DM, Sprent J, Surh CD. 146.  2007. Antiviral CD4+ memory T cells are IL-15 dependent. J. Exp. Med. 204:951–61 [Google Scholar]
  147. Bushar ND, Corbo E, Schmidt M, Maltzman JS, Farber DL. 147.  2010. Ablation of SLP-76 signaling after T cell priming generates memory CD4 T cells impaired in steady-state and cytokine-driven homeostasis. PNAS 107:827–31 [Google Scholar]
  148. Riou C, Yassine-Diab B, Van grevenynghe J, Somogyi R, Greller LD. 148.  et al. 2007. Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells. J. Exp. Med. 204:79–91 [Google Scholar]
  149. Li J, Huston G, Swain SL. 149.  2003. IL-7 promotes the transition of CD4 effectors to persistent memory cells. J. Exp. Med. 198:1807–15 [Google Scholar]
  150. Mazzucchelli RI, Warming S, Lawrence SM, Ishii M, Abshari M. 150.  et al. 2009. Visualization and identification of IL-7 producing cells in reporter mice. PLOS ONE 4:e7637 [Google Scholar]
  151. Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grun JR. 151.  et al. 2009. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30:721–30 [Google Scholar]
  152. Hara T, Shitara S, Imai K, Miyachi H, Kitano S. 152.  et al. 2012. Identification of IL-7-producing cells in primary and secondary lymphoid organs using IL-7-GFP knock-in mice. J. Immunol. 189:1577–84 [Google Scholar]
  153. Shinoda K, Tokoyoda K, Hanazawa A, Hayashizaki K, Zehentmeier S. 153.  et al. 2012. Type II membrane protein CD69 regulates the formation of resting T-helper memory. PNAS 109:7409–14 [Google Scholar]
  154. Hanazawa A, Hayashizaki K, Shinoda K, Yagita H, Okumura K. 154.  et al. 2013. CD49b-dependent establishment of T helper cell memory. Immunol. Cell Biol. 91:524–31 [Google Scholar]
  155. Feuerer M, Beckhove P, Mahnke Y, Hommel M, Kyewski B. 155.  et al. 2004. Bone marrow microenvironment facilitating dendritic cell: CD4 T cell interactions and maintenance of CD4 memory. Int. J. Oncol. 25:867–76 [Google Scholar]
  156. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG. 156.  et al. 2011. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477:216–19 [Google Scholar]
  157. Teijaro JR, Turner D, Pham Q, Wherry EJ, Lefrancois L, Farber DL. 157.  2011. Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187:5510–14 [Google Scholar]
  158. Hondowicz BD, An D, Schenkel JM, Kim KS, Steach HR. 158.  et al. 2016. Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma. Immunity 44:155–66 [Google Scholar]
  159. Shinoda K, Hirahara K, Iinuma T, Ichikawa T, Suzuki AS. 159.  et al. 2016. Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation. PNAS 113:E2842–51 [Google Scholar]
  160. Corris PA, Dark JH. 160.  1993. Aetiology of asthma: lessons from lung transplantation. Lancet 341:1369–71 [Google Scholar]
  161. Randall TD. 161.  2010. Bronchus-associated lymphoid tissue (BALT) structure and function. Adv. Immunol. 107:187–241 [Google Scholar]
  162. Van Dyken SJ, Nussbaum JC, Lee J, Molofsky AB, Liang H-E. 162.  et al. 2016. A tissue checkpoint regulates type 2 immunity. Nat. Immunol. 17:1381–87 [Google Scholar]
  163. Endo Y, Nakayama T. 163.  2015. Pathogenic Th2 (Tpath2) cells in airway inflammation. Oncotarget 6:32303–4 [Google Scholar]
  164. Mitson-Salazar A, Yin Y, Wansley DL, Young M, Bolan H. 164.  et al. 2016. Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human TH2 cell subpopulation with enhanced function. J. Allergy Clin. Immunol. 137:907–18.e9 [Google Scholar]
  165. Busse WW, Lemanske RF Jr. 165.  2001. Asthma. N. Engl. J. Med. 344:350–62 [Google Scholar]
  166. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W. 166.  et al. 2009. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360:973–84 [Google Scholar]
  167. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV. 167.  et al. 2011. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365:1088–98 [Google Scholar]
  168. Rothenberg ME. 168.  2016. Humanized anti-IL-5 antibody therapy. Cell 165:509 [Google Scholar]
  169. Kanno Y, Vahedi G, Hirahara K, Singleton K, O'Shea JJ. 169.  2012. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu. Rev. Immunol. 30:707–31 [Google Scholar]
  170. Watanabe Y, Onodera A, Kanai U, Ichikawa T, Obata-Ninomiya K. 170.  et al. 2014. Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells. PNAS 111:12829–34 [Google Scholar]
  171. Seumois G, Chavez L, Gerasimova A, Lienhard M, Omran N. 171.  et al. 2014. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. Nat. Immunol. 15:777–88 [Google Scholar]
  172. Smith ZD, Meissner A. 172.  2013. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14:204–20 [Google Scholar]
  173. Brand S, Kesper DA, Teich R, Kilic-Niebergall E, Pinkenburg O. 173.  et al. 2012. DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma. J. Allergy Clin. Immunol. 129:1602–10.e6 [Google Scholar]
  174. Yang IV, Pedersen BS, Liu A, O'Connor GT, Teach SJ. 174.  et al. 2015. DNA methylation and childhood asthma in the inner city. J. Allergy Clin. Immunol. 136:69–80 [Google Scholar]
  175. Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G. 175.  et al. 2012. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat. Immunol. 13:587–95 [Google Scholar]
  176. Pua HH, Steiner DF, Patel S, Gonzalez JR, Ortiz-Carpena JF. 176.  et al. 2016. MicroRNAs 24 and 27 suppress allergic inflammation and target a network of regulators of T helper 2 cell-associated cytokine production. Immunity 44:821–32 [Google Scholar]
  177. Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K. 177.  et al. 2012. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488:404–8 [Google Scholar]
  178. Akimoto T, Numata F, Tamura M, Takata Y, Higashida N. 178.  et al. 1998. Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice. J. Exp. Med. 187:1537–42 [Google Scholar]
  179. Knosp CA, Carroll HP, Elliott J, Saunders SP, Nel HJ. 179.  et al. 2011. SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses. J. Exp. Med. 208:1523–31 [Google Scholar]
  180. Yang XO, Zhang H, Kim BS, Niu X, Peng J. 180.  et al. 2013. The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat. Immunol. 14:732–40 [Google Scholar]
  181. Hawkins RD, Larjo A, Tripathi SK, Wagner U, Luu Y. 181.  et al. 2013. Global chromatin state analysis reveals lineage-specific enhancers during the initiation of human T helper 1 and T helper 2 cell polarization. Immunity 38:1271–84 [Google Scholar]
  182. Bergqvist A, Andersson CK, Hoffmann HJ, Mori M, Shikhagaie M. 182.  et al. 2013. Marked epithelial cell pathology and leukocyte paucity in persistently symptomatic severe asthma. Am. J. Respir. Crit. Care Med. 188:1475–77 [Google Scholar]
  183. Omori M, Yamashita M, Inami M, Ukai-Tadenuma M, Kimura M. 183.  et al. 2003. CD8 T cell-specific downregulation of histone hyperacetylation and gene activation of the IL-4 gene locus by ROG, repressor of GATA. Immunity 19:281–94 [Google Scholar]
  184. Hirahara K, Yamashita M, Iwamura C, Shinoda K, Hasegawa A. 184.  et al. 2008. Repressor of GATA regulates TH2-driven allergic airway inflammation and airway hyperresponsiveness. J. Allergy Clin. Immunol. 122:512–20.e11 [Google Scholar]
  185. Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM. 185.  et al. 2015. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N. Engl. J. Med. 372:1987–95 [Google Scholar]
  186. Donovan CE, Mark DA, He HZ, Liou HC, Kobzik L. 186.  et al. 1999. NF-κB/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation. J. Immunol. 163:6827–33 [Google Scholar]
  187. Kimura MY, Hosokawa H, Yamashita M, Hasegawa A, Iwamura C. 187.  et al. 2005. Regulation of T helper type 2 cell differentiation by murine Schnurri-2. J. Exp. Med. 201:397–408 [Google Scholar]
  188. Iwamura C, Kimura MY, Shinoda K, Endo Y, Hasegawa A. 188.  et al. 2007. Schnurri-2 regulates Th2-dependent airway inflammation and airway hyperresponsiveness. Int. Immunol. 19:755–62 [Google Scholar]
  189. Bruchard M, Rebe C, Derangere V, Togbe D, Ryffel B. 189.  et al. 2015. The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat. Immunol. 16:859–70 [Google Scholar]
  190. Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA. 190.  et al. 2013. BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis. Nature 498:506–10 [Google Scholar]
  191. Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J. 191.  et al. 2011. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378:1006–14 [Google Scholar]
  192. Hamilos DL. 192.  2015. Drivers of chronic rhinosinusitis: inflammation versus infection. J. Allergy Clin. Immunol. 136:1454–59 [Google Scholar]
  193. Bachert C, Vignola AM, Gevaert P, Leynaert B, Van Cauwenberge P, Bousquet J. 193.  2004. Allergic rhinitis, rhinosinusitis, and asthma: one airway disease. Immunol. Allergy Clin. North Am. 24:19–43 [Google Scholar]
  194. Nakayama T, Yoshikawa M, Asaka D, Okushi T, Matsuwaki Y. 194.  et al. 2011. Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis. Rhinology 49:392–96 [Google Scholar]
  195. Sakuma Y, Ishitoya J, Komatsu M, Shiono O, Hirama M. 195.  et al. 2011. New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis. Auris Nasus Larynx 38:583–88 [Google Scholar]
  196. Zhang N, Van Zele T, Perez-Novo C, Van Bruaene N, Holtappels G. 196.  et al. 2008. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J. Allergy Clin. Immunol. 122:961–68 [Google Scholar]
  197. Kim JW, Hong SL, Kim YK, Lee CH, Min YG, Rhee CS. 197.  2007. Histological and immunological features of non-eosinophilic nasal polyps. Otolaryngol. Head Neck Surg. 137:925–30 [Google Scholar]
  198. Cao PP, Li HB, Wang BF, Wang SB, You XJ. 198.  et al. 2009. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J. Allergy Clin. Immunol. 124:478–84, 84.e1–2 [Google Scholar]
  199. Iinuma T, Okamoto Y, Yamamoto H, Inamine-Sasaki A, Ohki Y. 199.  et al. 2015. Interleukin-25 and mucosal T cells in noneosinophilic and eosinophilic chronic rhinosinusitis. Ann. Allergy Asthma Immunol. 114:289–98 [Google Scholar]
  200. Seumois G, Zapardiel-Gonzalo J, White B, Singh D, Schulten V. 200.  et al. 2016. Transcriptional profiling of Th2 cells identifies pathogenic features associated with asthma. J. Immunol. 197:655–64 [Google Scholar]
  201. Weidinger S, Novak N. 201.  2016. Atopic dermatitis. Lancet 387:1109–22 [Google Scholar]
  202. Tenda Y, Yamashita M, Kimura MY, Hasegawa A, Shimizu C. 202.  et al. 2006. Hyperresponsive TH2 cells with enhanced nuclear factor-κB activation induce atopic dermatitis–like skin lesions in Nishiki-nezumi Cinnamon/Nagoya mice. J. Allergy Clin. Immunol. 118:725–33 [Google Scholar]
  203. Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T. 203.  et al. 2014. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N. Engl. J. Med. 371:130–39 [Google Scholar]
  204. Natsuaki Y, Egawa G, Nakamizo S, Ono S, Hanakawa S. 204.  et al. 2014. Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin. Nat. Immunol. 15:1064–69 [Google Scholar]
  205. Rothenberg ME. 205.  2004. Eosinophilic gastrointestinal disorders (EGID). J. Allergy Clin. Immunol. 113:11–28 [Google Scholar]
  206. Caldwell JM, Collins MH, Stucke EM, Putnam PE, Franciosi JP. 206.  et al. 2014. Histologic eosinophilic gastritis is a systemic disorder associated with blood and extragastric eosinophilia, TH2 immunity, and a unique gastric transcriptome. J. Allergy Clin. Immunol. 134:1114–24 [Google Scholar]
  207. Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B. 207.  et al. 2010. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. PNAS 107:8017–22 [Google Scholar]
  208. Seidelin JB, Bjerrum JT, Coskun M, Widjaya B, Vainer B, Nielsen OH. 208.  2010. IL-33 is upregulated in colonocytes of ulcerative colitis. Immunol. Lett. 128:80–85 [Google Scholar]
  209. De Salvo C, Wang XM, Pastorelli L, Mattioli B, Omenetti S. 209.  et al. 2016. IL-33 drives eosinophil infiltration and pathogenic type 2 helper T-cell immune responses leading to chronic experimental ileitis. Am. J. Pathol. 186:885–98 [Google Scholar]
  210. Nguyen LP, Pan J, Dinh TT, Hadeiba H, 3rd O'Hara E. 210.  et al. 2015. Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat. Immunol. 16:207–13 [Google Scholar]
  211. Mosmann TR, Sad S. 211.  1996. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol. Today 17:138–46 [Google Scholar]
  212. Singh VK, Mehrotra S, Agarwal SS. 212.  1999. The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy. Immunol. Res. 20:147–61 [Google Scholar]
  213. Antonelli A, Ferrari SM, Corrado A, Ferrannini E, Fallahi P. 213.  2014. CXCR3, CXCL10 and type 1 diabetes. Cytokine Growth Factor Rev 25:57–65 [Google Scholar]
  214. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ. 214.  et al. 2010. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467:967–71 [Google Scholar]
  215. Wambre E, DeLong JH, James EA, LaFond RE, Robinson D, Kwok WW. 215.  2012. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J. Allergy Clin. Immunol. 129:544–51.e7 [Google Scholar]
  216. Porter PC, Lim DJ, Maskatia ZK, Mak G, Tsai CL. 216.  et al. 2014. Airway surface mycosis in chronic TH2-associated airway disease. J. Allergy Clin. Immunol. 134:325–31 [Google Scholar]
  217. Kerzerho J, Maazi H, Speak AO, Szely N, Lombardi V. 217.  et al. 2013. Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity. J. Allergy Clin. Immunol. 131:1048–57.e2 [Google Scholar]
  218. Bauer M, Trupke J, Ringrose L. 218.  2016. The quest for mammalian Polycomb response elements: Are we there yet?. Chromosoma 125:471–96 [Google Scholar]
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