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Th1/Th2 Cell Differentiation and Molecular Signals

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T Helper Cell Differentiation and Their Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 841))

Abstract

The distinctive differentiated states of the CD4+ T helper cells are determined by the set of transcription factors and the genes transcribed by the transcription factors. In vitro induction models, the major determinants of the cytokines present during the T-cell receptor (TCR)-mediated activation process. IL-12 and IFN-γ make Naive CD4+ T cells highly express T-bet and STAT4 and differentiate to TH1 cells, while IL-4 make Naive CD4+ T cells highly express STAT6 and GATA3 and differentiated to TH2 cells. Even through T-bet and GATA3 are master regulators for TH1/TH2 cells differentiation. There are many other transcription factors, such as RUNX family proteins, IRF4, Dec2, Gfi1, Hlx, and JunB that can impair TH1/TH2 cells differentiation. In recent years, noncoding RNAs (microRNA and long noncoding RNA) join in the crowd. The leukocytes should migrate to the right place to show their impact. There are some successful strategies, which are revealed to targeting chemokines and their receptors, that have been developed to treat human immune-related diseases.

An erratum to this chapter is available at DOI 10.1007/978-94-017-9487-9_9.

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-94-017-9487-9_9

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References

  1. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM (2002) T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol 3:549–557

    CAS  PubMed  Google Scholar 

  2. Alatrakchi N, Koziel M (2009) Regulatory T cells and viral liver disease. J Viral Hepat 16:223–229

    PubMed  Google Scholar 

  3. Alexander CM, Tygrett LT, Boyden AW, Wolniak KL, Legge KL, Waldschmidt TJ (2011) T regulatory cells participate in the control of germinal centre reactions. Immunology 133:452–468

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Aliberti J, Valenzuela JG, Carruthers VB, Hieny S, Andersen J, Charest H, Reis e Sousa C, Fairlamb A, Ribeir JM, Sher A (2003) Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol 4:485–490

    CAS  PubMed  Google Scholar 

  5. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955–1958

    CAS  PubMed  Google Scholar 

  6. Allen SJ, Crown SE, Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787–820

    CAS  PubMed  Google Scholar 

  7. Alonzo F 3rd, Kozhaya L, Rawlings SA, Reyes-Robles T, DuMont AL, Myszka DG, Landau NR, Unutmaz D, Torres VJ (2013) CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature 493:51–55

    PubMed  Google Scholar 

  8. Atchley WR, Fitch WM (1997) A natural classification of the basic helix-loop-helix class of transcription factors. Proc Natl Acad Sci USA 94:5172–5176

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A (2002) T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 3:643–651

    CAS  PubMed  Google Scholar 

  10. Baggiolini M, Dewald B, Moser B (1994) Interleukin-8 and related chemotactic cytokines–CXC and CC chemokines. Adv Immunol 55:97–179

    CAS  PubMed  Google Scholar 

  11. Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36:847–856

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Bandeira-Melo C, Sugiyama K, Woods LJ, Phoofolo M, Center DM, Cruikshank WW, Weller PF (2002) IL-16 promotes leukotriene C(4) and IL-4 release from human eosinophils via CD4- and autocrine CCR3-chemokine-mediated signaling. J Immunol 168:4756–4763

    CAS  PubMed  Google Scholar 

  13. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837

    CAS  PubMed  Google Scholar 

  14. Baumjohann D, Ansel KM (2013) MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 13:666–678

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, Kuchroo VK (2009) 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 10:167–175

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Boehm T (2011) Design principles of adaptive immune systems. Nat Rev Immunol 11:307–317

    CAS  PubMed  Google Scholar 

  17. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187:129–134

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25:1915–1927

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Cai G, Radzanowski T, Villegas EN, Kastelein R, Hunter CA (2000) Identification of STAT4-dependent and independent mechanisms of resistance to Toxoplasma gondii. J Immunol 165:2619–2627

    CAS  PubMed  Google Scholar 

  20. Campbell JJ, Brightling CE, Symon FA, Qin S, Murphy KE, Hodge M, Andrew DP, Wu L, Butcher EC, Wardlaw AJ (2001) Expression of chemokine receptors by lung T cells from normal and asthmatic subjects. J Immunol 166:2842–2848

    CAS  PubMed  Google Scholar 

  21. Charo IF, Myers SJ, Herman A, Franci C, Connolly AJ, Coughlin SR (1994) Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci USA 91:2752–2756

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116:1317–1326

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Chensue SW, Lukacs NW, Yang TY, Shang X, Frait KA, Kunkel SL, Kung T, Wiekowski MT, Hedrick JA, Cook DN, Zingoni A, Narula SK, Zlotnik A, Barrat FJ, O’Garra A, Napolitano M, Lira SA (2001) Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J Exp Med 193:573–584

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Chi H (2011) Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol Sci 32:16–24

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135–1148

    CAS  PubMed  Google Scholar 

  26. Choi YS, Yang JA, Crotty S (2013) Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells. Curr Opin Immunol 25:366–372

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Cimmino L, Martins GA, Liao J, Magnusdottir E, Grunig G, Perez RK, Calame KL (2008) Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression. J Immunol 181:2338–2347

    CAS  PubMed  Google Scholar 

  28. Cobb BS, Nesterova TB, Thompson E, Hertweck A, O’Connor E, Godwin J, Wilson CB, Brockdorff N, Fisher AG, Smale ST, Merkenschlager M (2005) T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J Exp Med 201:1367–1373

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, Gladue RP, Lin W, Boyd JG, Moser B, Wood DE, Sahagan BG, Neote K (1998) Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med 187:2009–2021

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM (2012) Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol 189:2084–2088

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Contreras J, Rao DS (2012) MicroRNAs in inflammation and immune responses. Leukemia 26:404–413

    CAS  PubMed  Google Scholar 

  32. Cosmi L, Maggi L, Santarlasci V, Liotta F, Annunziato F (2014) T helper cells plasticity in inflammation. Cytometry A 85:36–42

    PubMed  Google Scholar 

  33. Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA, Hu-Li J, Zhu J, Paul WE (2004) Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci USA 101:3880–3885

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Crotty S, Johnston RJ, Schoenberger SP (2010) Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 11:114–120

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748

    CAS  PubMed  Google Scholar 

  36. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O’Brien SJ (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia growth and development study, multicenter AIDS cohort study, multicenter hemophilia cohort study, San Francisco City cohort, alive study. Science 273:1856–1862

    CAS  PubMed  Google Scholar 

  37. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666

    CAS  PubMed  Google Scholar 

  38. Derrien T, Guigo R, Johnson R (2011) The long non-coding RNAs: a new (P)layer in the “dark matter”. Front Genet 2:107

    PubMed Central  PubMed  Google Scholar 

  39. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Dobner T, Wolf I, Emrich T, Lipp M (1992) Differentiation-specific expression of a novel G protein-coupled receptor from Burkitt’s lymphoma. Eur J Immunol 22:2795–2799

    CAS  PubMed  Google Scholar 

  41. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381:667–673

    CAS  PubMed  Google Scholar 

  42. Duan Z, Horwitz M (2005) Gfi-1 takes center stage in hematopoietic stem cells. Trends Mol Med. 11:49–52

    CAS  PubMed  Google Scholar 

  43. Egawa T, Tillman RE, Naoe Y, Taniuchi I, Littman DR (2007) The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J Exp Med 204:1945–1957

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Eisman R, Surrey S, Ramachandran B, Schwartz E, Poncz M (1990) Structural and functional comparison of the genes for human platelet factor 4 and PF4alt. Blood 76:336–344

    CAS  PubMed  Google Scholar 

  45. Endo Y, Iwamura C, Kuwahara M, Suzuki A, Sugaya K, Tumes DJ, Tokoyoda K, Hosokawa H, Yamashita M, Nakayama T (2011) Eomesodermin controls interleukin-5 production in memory T helper 2 cells through inhibition of activity of the transcription factor GATA3. Immunity 35:733–745

    CAS  PubMed  Google Scholar 

  46. Farzan M, Mirzabekov T, Kolchinsky P, Wyatt R, Cayabyab M, Gerard NP, Gerard C, Sodroski J, Choe H (1999) Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96:667–676

    CAS  PubMed  Google Scholar 

  47. Finkelman FD, Morris SC, Orekhova T, Mori M, Donaldson D, Reiner SL, Reilly NL, Schopf L, Urban JF Jr (2000) Stat6 regulation of in vivo IL-4 responses. J Immunol 164:2303–2310

    CAS  PubMed  Google Scholar 

  48. Foster TJ (2005) Immune evasion by staphylococci. Nat Rev Microbiol 3:948–958

    CAS  PubMed  Google Scholar 

  49. Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Hollander GA, Piali L (2002) Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med 8:1414–1420

    CAS  PubMed  Google Scholar 

  50. Frucht DM, Aringer M, Galon J, Danning C, Brown M, Fan S, Centola M, Wu CY, Yamada N, El Gabalawy H, O’Shea JJ (2000) Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol 164:4659–4664

    CAS  PubMed  Google Scholar 

  51. Fujimoto K, Shen M, Noshiro M, Matsubara K, Shingu S, Honda K, Yoshida E, Suardita K, Matsuda Y, Kato Y (2001) Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins. Biochem Biophys Res Commun 280:164–171

    CAS  PubMed  Google Scholar 

  52. Garriga-Canut M, Roopra A, Buckley NJ (2001) The basic helix-loop-helix protein, sharp-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism. J Biol Chem 276:14821–14828

    CAS  PubMed  Google Scholar 

  53. Georgopoulos K, Winandy S, Avitahl N (1997) The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol 15:155–176

    CAS  PubMed  Google Scholar 

  54. Gilks CB, Bear SE, Grimes HL, Tsichlis PN (1993) Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein. Mol Cell Biol 13:1759–1768

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard K (2013) The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152:743–754

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Gorelik L, Fields PE, Flavell RA (2000) Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 165:4773–4777

    CAS  PubMed  Google Scholar 

  57. Green CJ, Charles RS, Edwards BF, Johnson PH (1989) Identification and characterization of PF4varl, a human gene variant of platelet factor 4. Mol Cell Biol 9:1445–1451

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Grenningloh R, Kang BY, Ho IC (2005) Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses. J Exp Med 201:615–626

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Grigorova IL, Schwab SR, Phan TG, Pham TH, Okada T, Cyster JG (2009) Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol 10:58–65

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Grogan JL, Mohrs M, Harmon B, Lacy DA, Sedat JW, Locksley RM (2001) Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14:205–215

    CAS  PubMed  Google Scholar 

  61. Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE (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 172:921–929

    PubMed  Google Scholar 

  62. Gulati A, Sacchetti M, Bonini S, Dana R (2006) Chemokine receptor CCR5 expression in conjunctival epithelium of patients with dry eye syndrome. Arch Ophthalmol 124:710–716

    CAS  PubMed  Google Scholar 

  63. Guo L, Wei G, Zhu J, Liao W, Leonard WJ, Zhao K, Paul W (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci USA 106:13463–13468

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    CAS  PubMed  Google Scholar 

  65. He Y, Jones CR, Fujiki N, Xu Y, Guo B, Holder JL Jr, Rossner MJ, Nishino S, Fu YH (2009) The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325:866–870

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Hobson JP, Rosenfeldt HM, Barak LS, Olivera A, Poulton S, Caron MG, Milstien S, Spiegel S (2001) Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291:1800–1803

    CAS  PubMed  Google Scholar 

  67. Hsieh CS, Heimberger AB, Gold JS, O’Garra A, Murphy KM (1992) Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci USA 89:6065–6069

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM (1993) Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547–549

    CAS  PubMed  Google Scholar 

  69. Hu G, Tang Q, Sharma S, Yu F, Escobar TM, Muljo SA, Zhu J, Zhao K (2013) Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat Immunol 14:1190–1198

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Huffaker TB, Hu R, Runtsch MC, Bake E, Chen X, Zhao J, Round JL, Baltimore D, O’Connell RM (2012) Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep 2:1697–1709

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH (2005) T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307:430–433

    CAS  PubMed  Google Scholar 

  72. Hwang ES, White IA, Ho IC (2002) An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines. Proc Natl Acad Sci USA 99:13026–13030

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O (1997) The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J Biol Chem 272:15036–15042

    CAS  PubMed  Google Scholar 

  74. Imai T, Chantry D, Raport CJ, Wood CL, Nishimura M, Godiska R, Yoshie O, Gray PW (1998) Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J Biol Chem 273:1764–1768

    CAS  PubMed  Google Scholar 

  75. Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N, Yel L, Forveille M, Kavli B, Krokan HE, Ochs HD, Fischer A, Durandy A (2003) Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 4:1023–1028

    CAS  PubMed  Google Scholar 

  76. Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, Murphy KM (2011) The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol 12:536–543

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458:524–528

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Islam SA, Chang DS, Colvin RA, Byrne MH, McCully ML, Moser B, Lira SA, Charo IF, Luster AD (2011) Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+T(H)2 cells. Nat Immunol 12:167–177

    CAS  PubMed  Google Scholar 

  79. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325:1006–1010

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R (2005) Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306:343–348

    CAS  PubMed  Google Scholar 

  81. Kaplan MH, Schindler U, Smiley ST, Grusby MJ (1996) Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4:313–319

    CAS  PubMed  Google Scholar 

  82. Kaplan MH, Sun YL, Hoey T, Grusby MJ (1996) Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382:174–177

    CAS  PubMed  Google Scholar 

  83. Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, Butcher EC (2001) Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest 108:1331–1339

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M, Lin C, Socci ND, Hermida L, Fulci V, Chiaretti S, Foa R, Schliwka J, Fuchs U, Novosel A, Muller RU, Schermer B, Bissels U, Inman J, Phan Q, Chien M, Weir DB, Choksi R, De Vita G, Frezzetti D, Trompeter HI, Hornung V, Teng G, Hartmann G, Palkovits M, Di Lauro R, Wernet P, Macino G, Rogler CE, Nagle JW, Ju J, Papavasiliou FN, Benzing T, Lichter P, Tam W, Brownstein MJ, Bosio A, Borkhardt A, Russo JJ, Sander C, Zavolan M, Tuschl T (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P (2003) An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J Exp Med 197:1537–1549

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleev R, Spiegel S, Hla T (1998) Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279:1552–1555

    CAS  PubMed  Google Scholar 

  88. Lee GR, Fields PE, Flavell RA (2001) Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14:447–459

    CAS  PubMed  Google Scholar 

  89. Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O’Garra A, Arai N (2000) GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med 192:105–115

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Li B, Tournier C, Davis RJ, Flavell RA (1999) Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 18:420–432

    PubMed Central  PubMed  Google Scholar 

  91. Li Z, Zhang Y, Liu Z, Wu X, Zheng Y, Tao Z, Mao K, Wang J, Lin G, Tian L, Ji Y, Qin M, Sun S, Zhu X, Sun B (2011) ECM1 controls T(H)2 cell egress from lymph nodes through re-expression of S1P(1). Nat Immunol 12:178–185

    CAS  PubMed  Google Scholar 

  92. Liao W, Schones DE, Oh J, Cui Y, Cui K, Roh TY, Zhao K, Leonard WJ (2008) Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol 9:1288–1296

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, Nguyen BV, Gadina M, Sher A, Paul WE, O’Shea JJ (2001) T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA 98:15137–15142

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Liu Z, Li Z, Mao K, Zou J, Wang Y, Tao Z, Lin G, Tian L, Ji Y, Wu X, Zhu X, Sun S, Chen W, Xiang C, Sun B (2009) Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling. J Immunol 183:6320–6329

    CAS  PubMed  Google Scholar 

  95. Liu J, Liu S, Cao X (2012) Highlights of the advances in basic immunology in 2011. Cell Mol Immunol 9:197–207

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Liu H, Toman RE, Goparaju SK, Maceyka M, Nava VE, Sankala H, Payne SG, Bektas M, Ishii I, Chun J, Milstien S, Spiegel S (2003) Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem 278:40330–40336

    CAS  PubMed  Google Scholar 

  97. Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B (1996) Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 184:963–969

    CAS  PubMed  Google Scholar 

  98. Loetscher M, Loetscher P, Brass N, Meese E, Moser B (1998) Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 28:3696–3705

    CAS  PubMed  Google Scholar 

  99. Lynch EA, Heijens CA, Horst NF, Center DM, Cruikshank WW (2003) Cutting edge: IL-16/CD4 preferentially induces Th1 cell migration: requirement of CCR5. J Immunol 171:4965–4968

    CAS  PubMed  Google Scholar 

  100. Maceyka M, Sankala H, Hait NC, Le Stunff H, Liu H, Toman R, Collier C, Zhang M, Satin LS, Merrill AH Jr, Milstien S, Spiegel S (2005) SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 280:37118–37129

    CAS  PubMed  Google Scholar 

  101. Marangoni F, Murooka TT, Manzo T, Kim EY, Carrizosa E, Elpek NM, Mempel TR (2013) The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells. Immunity 38:237–249

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Marchese A, Heiber M, Nguyen T, Heng HH, Saldivia VR, Cheng R, Murphy PM, Tsui LC, Shi X, Gregor P et al (1995) Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors. Genomics 29:335–344

    CAS  PubMed  Google Scholar 

  103. Martins G, Calame K (2008) Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol 26:133–169

    CAS  PubMed  Google Scholar 

  104. Martins GA, Cimmino L, Liao J, Magnusdottir E, Calame K (2008) Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J Exp Med 205:1959–1965

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Martins GA, Cimmino L, Shapiro-Shelef M, Szabolcs M, Herron A, Magnusdottir E, Calame K (2006) Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 7:457–465

    CAS  PubMed  Google Scholar 

  106. Merkenschlager M, Wilson CB (2008) RNAi and chromatin in T cell development and function. Curr Opin Immunol 20:131–138

    CAS  PubMed  Google Scholar 

  107. Mikhak Z, Fukui M, Farsidjani A, Medoff BD, Tager AM, Luster AD (2009) Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation. J Allergy Clin Immunol 123(67–73):e3

    PubMed  Google Scholar 

  108. Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC (2007) Ets-1 is a negative regulator of Th17 differentiation. J Exp Med 204:2825–2835

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357

    CAS  PubMed  Google Scholar 

  110. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    CAS  PubMed  Google Scholar 

  111. Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K (2005) Aberrant T cell differentiation in the absence of Dicer. J Exp Med 202:261–269

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907–1910

    CAS  PubMed  Google Scholar 

  113. Mullen AC, Hutchins AS, High FA, Lee HW, Sykes KJ, Chodosh LA, Reiner SL (2002) Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nat Immunol 3:652–658

    CAS  PubMed  Google Scholar 

  114. Mummidi S, Ahuja SS, McDaniel BL, Ahuja SK (1997) The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5′-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons. J Biol Chem 272:30662–30671

    CAS  PubMed  Google Scholar 

  115. Murre C (2005) Helix-loop-helix proteins and lymphocyte development. Nat Immunol 6:1079–1086

    CAS  PubMed  Google Scholar 

  116. Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O (1999) Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 6:337–345

    CAS  PubMed  Google Scholar 

  117. Nakanishi Y, Lu B, Gerard C, Iwasaki A (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462:510–513

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Neote K, DiGregorio D, Mak JY, Horuk R, Schall TJ (1993) Molecular cloning, functional expression, and signaling characteristics of a C–C chemokine receptor. Cell 72:415–425

    CAS  PubMed  Google Scholar 

  119. Okada T, Ding G, Sonoda H, Kajimoto T, Haga Y, Khosrowbeygi A, Gao S, Miwa N, Jahangeer S, Nakamura S (2005) Involvement of N-terminal-extended form of sphingosine kinase 2 in serum-dependent regulation of cell proliferation and apoptosis. J Biol Chem 280:36318–36325

    CAS  PubMed  Google Scholar 

  120. Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T, Miyachi Y, Tsukada T, Sakaguchi S (2007) Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446:685–689

    CAS  PubMed  Google Scholar 

  121. Ouyang W, Lohning M, Gao Z, Assenmacher M, Ranganath S, Radbruch A, Murphy KM (2000) Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12:27–37

    CAS  PubMed  Google Scholar 

  122. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM (1998) Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9:745–755

    CAS  PubMed  Google Scholar 

  123. Pagani M, Rossetti G, Panzeri I, de Candia P, Bonnal RJ, Rossi RL, Geginat J, Abrignani S (2013) Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation. Immunol Rev 253:82–96

    PubMed  Google Scholar 

  124. Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF, Jinasena D, Sharma SM, McCadden EM, Getnet D, Drake CG, Liu JO, Ostrowski MC, Pardoll DM (2009) Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325:1142–1146

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, Coughlin SR (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316:295–298

    CAS  PubMed  Google Scholar 

  126. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Paul WE, Seder RA (1994) Lymphocyte responses and cytokines. Cell 76:241–251

    CAS  PubMed  Google Scholar 

  128. Pereira JP, Kelly LM, Cyster JG (2010) Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int Immunol 22:413–419

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Perros F, Hoogsteden HC, Coyle AJ, Lambrecht BN, Hammad H (2009) Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy 64:995–1002

    CAS  PubMed  Google Scholar 

  130. Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ, Pappu R, Coughlin SR, McDonald DM, Schwab SR, Cyster JG (2010) Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J Exp Med 207:17–27

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Ponjavic J, Ponting CP (2007) The long and the short of RNA maps. BioEssays 29:1077–1080

    CAS  PubMed  Google Scholar 

  132. Ponjavic J, Ponting CP, Lunter G (2007) Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. Genome Res 17:556–565

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Power CA, Meyer A, Nemeth K, Bacon KB, Hoogewerf AJ, Proudfoot AE, Wells TN (1995) Molecular cloning and functional expression of a novel CC chemokine receptor cDNA from a human basophilic cell line. J Biol Chem 270:19495–19500

    CAS  PubMed  Google Scholar 

  134. Pulendran B, Artis D (2012) New paradigms in type 2 immunity. Science 337:431–435

    PubMed Central  CAS  PubMed  Google Scholar 

  135. Quirion MR, Gregory GD, Umetsu SE, Winandy S, Brown MA (2009) Cutting edge: Ikaros is a regulator of Th2 cell differentiation. J Immunol 182:741–745

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Reiner SL, Locksley RM (1995) The regulation of immunity to Leishmania major. Annu Rev Immunol 13:151–177

    CAS  PubMed  Google Scholar 

  137. Rivera J, Proia RL, Olivera A (2008) The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8:753–763

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Rivino L, Messi M, Jarrossay D, Lanzavecchia A, Sallusto F, Geginat J (2004) Chemokine receptor expression identifies Pre-T helper (Th)1, Pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J Exp Med 200:725–735

    PubMed Central  CAS  PubMed  Google Scholar 

  139. Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley SB, Menon S, Kastelein R, Bazan F, O’Garra A (1997) IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity 7:571–581

    CAS  PubMed  Google Scholar 

  140. Rossi RL, Rossetti G, Wenandy L, Curti S, Ripamonti A, Bonnal RJ, Birolo RS, Moro M, Crosti MC, Gruarin P, Maglie S, Marabita F, Mascheroni D, Parente V, Comelli M, Trabucchi E, De Francesco R, Geginat J, Abrignani S, Pagani M (2011) Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. Nat Immunol 12:796–803

    CAS  PubMed  Google Scholar 

  141. Rot A, von Andrian UH (2004) Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22:891–928

    CAS  PubMed  Google Scholar 

  142. Rottman JB, Ganley KP, Williams K, Wu L, Mackay CR, Ringler DJ (1997) Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am J Pathol 151:1341–1351

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 187:875–883

    PubMed Central  CAS  PubMed  Google Scholar 

  144. Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M (1996) Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35:3362–3367

    CAS  PubMed  Google Scholar 

  145. Sato T, Komai M, Iwase M, Kobayashi K, Tahara H, Ohshima E, Arai H, Miki I (2009) Inhibitory effect of the new orally active CCR4 antagonist K327 on CCR4+ CD4+ T cell migration into the lung of mice with ovalbumin-induced lung allergic inflammation. Pharmacology 84:171–182

    CAS  PubMed  Google Scholar 

  146. Schaumberg DA, Sullivan DA, Buring JE, Dana MR (2003) Prevalence of dry eye syndrome among US women. Am J Ophthalmol 136:318–326

    PubMed  Google Scholar 

  147. Schwab SR, Cyster JG (2007) Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 8:1295–1301

    CAS  PubMed  Google Scholar 

  148. Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309:1735–1739

    CAS  PubMed  Google Scholar 

  149. Seder RA, Paul WE, Davis MM, de St Fazekas, Groth B (1992) The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med 176:1091–1098

    CAS  PubMed  Google Scholar 

  150. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–633

    CAS  PubMed  Google Scholar 

  151. Spiegel S, Milstien S (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11:403–415

    PubMed Central  CAS  PubMed  Google Scholar 

  152. Spilianakis CG, Flavell RA (2004) Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat Immunol 5:1017–1027

    CAS  PubMed  Google Scholar 

  153. Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33:192–202

    CAS  PubMed  Google Scholar 

  154. Struyf S, Burdick MD, Proost P, Van Damme J, Strieter RM (2004) Platelets release CXCL4L1, a nonallelic variant of the chemokine platelet factor-4/CXCL4 and potent inhibitor of angiogenesis. Circ Res 95:855–857

    CAS  PubMed  Google Scholar 

  155. Struyf S, Salogni L, Burdick MD, Vandercappellen J, Gouwy M, Noppen S, Proost P, Opdenakker G, Parmentier M, Gerard C, Sozzani S, Strieter RM, Van Damme J (2011) Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3. Blood 117:480–488

    PubMed Central  CAS  PubMed  Google Scholar 

  156. Swain SL, Weinberg AD, English M, Huston G (1990) IL-4 directs the development of Th2-like helper effectors. J Immunol 145:3796–3806

    CAS  PubMed  Google Scholar 

  157. Syrbe U, Siveke J, Hamann A (1999) Th1/Th2 subsets: distinct differences in homing and chemokine receptor expression? Springer Semin Immunopathol 21:263–285

    CAS  PubMed  Google Scholar 

  158. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669

    CAS  PubMed  Google Scholar 

  159. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH (2003) Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 21:713–758

    CAS  PubMed  Google Scholar 

  160. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH (2002) Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295:338–342

    CAS  PubMed  Google Scholar 

  161. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S (1996) Essential role of Stat6 in IL-4 signalling. Nature 380:627–630

    CAS  PubMed  Google Scholar 

  162. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T, Ito Y, Littman DR (2002) Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111:621–633

    CAS  PubMed  Google Scholar 

  163. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174

    CAS  PubMed  Google Scholar 

  164. Tornwall J, Lane TE, Fox RI, Fox HS (1999) T cell attractant chemokine expression initiates lacrimal gland destruction in nonobese diabetic mice. Lab Invest 79:1719–1726

    CAS  PubMed  Google Scholar 

  165. Usui T, Nishikomori R, Kitani A, Strober W (2003) GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rbeta2 chain or T-bet. Immunity 18:415–428

    CAS  PubMed  Google Scholar 

  166. Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O’Shea JJ, Strober W (2006) T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med 203:755–766

    PubMed Central  CAS  PubMed  Google Scholar 

  167. Vandercappellen J, Noppen S, Verbeke H, Put W, Conings R, Gouwy M, Schutyser E, Proost P, Sciot R, Geboes K, Opdenakker G, Van Damme J, Struyf S (2007) Stimulation of angiostatic platelet factor-4 variant (CXCL4L1/PF-4var) versus inhibition of angiogenic granulocyte chemotactic protein-2 (CXCL6/GCP-2) in normal and tumoral mesenchymal cells. J Leukoc Biol 82:1519–1530

    CAS  PubMed  Google Scholar 

  168. Verzijl D, Peters SL, Alewijnse AE (2010) Sphingosine-1-phosphate receptors: zooming in on ligand-induced intracellular trafficking and its functional implications. Mol Cells 29:99–104

    CAS  PubMed  Google Scholar 

  169. Viola A, Luster AD (2008) Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 48:171–197

    CAS  PubMed  Google Scholar 

  170. Wan YY (2010) Multi-tasking of helper T cells. Immunology 130:166–171

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Wang J, Fathman JW, Lugo-Villarino G, Scimone L, von Andrian U, Dorfman DM, Glimcher LH (2006) Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest 116:414–421

    PubMed Central  CAS  PubMed  Google Scholar 

  172. Wei G, Abraham BJ, Yagi R, Jothi R, Cui K, Sharma S, Narlikar L, Northrup DL, Tang Q, Paul WE, Zhu J, Zhao K (2011) Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35:299–311

    PubMed Central  CAS  PubMed  Google Scholar 

  173. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT, Schones DE, Peng W, Sun HW, Paul WE, O’Shea JJ, Zhao K (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155–167

    PubMed Central  PubMed  Google Scholar 

  174. Weinreich MA, Takada K, Skon C, Reiner SL, Jameson SC, Hogquist KA (2009) KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity 31:122–130

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Wilson CB, Rowell E, Sekimata M (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9:91–105

    CAS  PubMed  Google Scholar 

  176. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, Henderson JM, Kutok JL, Rajewsky K (2008) Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 9:405–414

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Yamamoto J, Adachi Y, Onoue Y, Adachi YS, Okabe Y, Itazawa T, Toyoda M, Seki T, Morohashi M, Matsushima K, Miyawaki T (2000) Differential expression of the chemokine receptors by the Th1- and Th2-type effector populations within circulating CD4+ T cells. J Leukoc Biol 68:568–574

    CAS  PubMed  Google Scholar 

  178. Yamane H, Zhu J, Paul WE (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

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Yang XO, Angkasekwinai P, Zhu J, Peng J, Liu Z, Nurieva R, Liu X, Chung Y, Chang SH, Sun B, Dong C (2009) Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol 10:1260–1266

    PubMed Central  CAS  PubMed  Google Scholar 

  180. Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM (2001) IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced. IFN-gamma production. Nat Immunol 2:157–164

    CAS  Google Scholar 

  181. Zagury D, Lachgar A, Chams V, Fall LS, Bernard J, Zagury JF, Bizzini B, Gringeri A, Santagostino E, Rappaport J, Feldman M, O’Brien SJ, Burny A, Gallo RC (1998) C–C chemokines, pivotal in protection against HIV type 1 infection. Proc Natl Acad Sci USA 95:3857–3861

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Zeng WP (2013) ‘All things considered’: transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation. Immunology 140:31–38

    PubMed Central  CAS  PubMed  Google Scholar 

  183. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A (1997) Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 272:21597–21603

    CAS  PubMed  Google Scholar 

  184. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356

    PubMed Central  CAS  PubMed  Google Scholar 

  185. Zhu J, Cote-Sierra J, Guo L, Paul WE (2003) Stat5 activation plays a critical role in Th2 differentiation. Immunity 19:739–748

    CAS  PubMed  Google Scholar 

  186. Zhu J, Davidson TS, Wei G, Jankovic D, Cui K, Schones DE, Guo L, Zhao K, Shevach EM, Paul WE (2009) Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J Exp Med 206:329–341

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Zhu J, Guo L, Min B, Watson CJ, Hu-Li J, Young HA, Tsichlis PN, Paul WE (2002) Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. Immunity 16:733–744

    CAS  PubMed  Google Scholar 

  188. Zhu J, Guo L, Watson CJ, Hu-Li J, Paul WE (2001) Stat6 is necessary and sufficient for IL-4’s role in Th2 differentiation and cell expansion. J Immunol. 166:7276–7281

    CAS  PubMed  Google Scholar 

  189. Zhu J, Jankovic D, Grinberg A, Guo L, Paul WE (2006) Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc Natl Acad Sci USA 103:18214–18219

    PubMed Central  CAS  PubMed  Google Scholar 

  190. Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, Killeen N, Urban JF Jr, Guo L, Paul WE (2004) Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol 5:1157–1165

    CAS  PubMed  Google Scholar 

  191. Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238:247–262

    PubMed Central  CAS  PubMed  Google Scholar 

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    Yuan Zhang, Yaguang Zhang, Wangpeng Gu & Bing Sun

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Zhang, Y., Zhang, Y., Gu, W., Sun, B. (2014). Th1/Th2 Cell Differentiation and Molecular Signals. In: Sun, B. (eds) T Helper Cell Differentiation and Their Function. Advances in Experimental Medicine and Biology, vol 841. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9487-9_2

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