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PMID: 23668241 Published · ppublish English Journal Article Review

'All things considered': transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation.

Immunology ·Vol. 140 ·No. 1 ·2013-09-00 ·Pages 31-8

Zeng WP

Abstract

T helper type 2 (Th2) cells are critical to host defence against helminth infection and the pathogenesis of allergic diseases. The differentiation of Th2 cells from naive CD4 T cells is controlled by intricate transcriptional mechanisms. At the precursor stage of naive CD4 T cells, transcriptional mechanisms maintain the potential and in the meantime prevent spontaneous differentiation to Th2 fate. In addition, intrachromosomal interactions important for co-ordinated expression of Th2 cytokines pre-exist in naive CD4 T cells. Upon T-cell receptor (TCR) engagement, naive CD4 T cells are induced by polarizing signals of the interleukin-4/Stat6 and Jagged/Notch pathways to up-regulate the expression of GATA-3. Once up-regulated, GATA-3 drives Th2 and suppresses Th1 differentiation in a cell autonomous fashion. In this stage of differentiation, the Th2 cytokine locus, as well as the interferon-γ locus, undergoes chromatin remodelling and epigenetic modifications that contribute to the somatic memory of Th2 cytokine gene expression pattern. Once differentiated, Th2 effector cells promptly produce Th2 cytokines upon TCR stimulation, which is regulated by concerted actions of GATA-3, TCR signalling, enhancers and the Th2 locus control region. This review provides a detailed account of the transcriptional regulatory events at these different stages of Th2 differentiation.

Keywords
CD4/Helper T cells cytokines transcription factors
MeSH Terms
Animals Calcium-Binding Proteins/metabolism Cell Differentiation/genetics,immunology Chromatin Assembly and Disassembly Chromosome Mapping Cytokines/genetics Epigenesis, Genetic GATA3 Transcription Factor/metabolism Gene Regulatory Networks Humans Intercellular Signaling Peptides and Proteins/metabolism Interleukin-4/metabolism Jagged-1 Protein Lymphocyte Activation Membrane Proteins/metabolism Receptors, Antigen, T-Cell/metabolism Receptors, Notch/metabolism STAT6 Transcription Factor/metabolism Serrate-Jagged Proteins Signal Transduction Th1 Cells/cytology,immunology Th2 Cells/cytology,immunology,metabolism
Chemicals
Calcium-Binding Proteins Cytokines GATA3 Transcription Factor Intercellular Signaling Peptides and Proteins JAG1 protein, human Jagged-1 Protein Membrane Proteins Receptors, Antigen, T-Cell Receptors, Notch STAT6 Transcription Factor Serrate-Jagged Proteins Interleukin-4
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Zeng Wei-ping
Department of Biochemistry and Microbiology, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USA. zengw@marshall.edu
References (99)
99 references, click to expand
  1. Regulation of the Th2 cytokine locus by a locus control region.
    Immunity. 2003 Jul;19(1):145-53 PMID: 12871646
  2. Disruption of the murine IL-4 gene blocks Th2 cytokine responses.
    Nature. 1993 Mar 18;362(6417):245-8 PMID: 8384701
  3. The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation.
    Immunity. 2012 Oct 19;37(4):622-33 PMID: 23041065
  4. Notch directly regulates Gata3 expression during T helper 2 cell differentiation.
    Immunity. 2007 Jul;27(1):100-10 PMID: 17658278
  5. ROG, repressor of GATA, regulates the expression of cytokine genes.
    Immunity. 2000 Mar;12(3):323-33 PMID: 10755619
  6. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3.
    J Immunol. 2001 Oct 15;167(8):4414-20 PMID: 11591766
  7. The IL-4 production capability of different strains of naive CD4(+) T cells controls the direction of the T(h) cell response.
    Int Immunol. 2002 Jan;14(1):1-11 PMID: 11751746
  8. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation.
    Immunity. 1998 Dec;9(6):765-75 PMID: 9881967
  9. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment.
    Nat Immunol. 2009 Dec;10(12):1260-6 PMID: 19881507
  10. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite.
    J Exp Med. 2004 Aug 16;200(4):507-17 PMID: 15314076
  11. Evolutionarily conserved sequence elements that positively regulate IFN-gamma expression in T cells.
    Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12622-7 PMID: 15304658
  12. 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 Immunol. 2008 Sep 1;181(5):2943-51 PMID: 18713964
  13. Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production.
    J Immunol. 2010 Sep 15;185(6):3489-97 PMID: 20702731
  14. Transcriptional regulation by STAT6.
    Immunol Res. 2011 May;50(1):87-96 PMID: 21442426
  15. Mast cell production of IL-4 and TNF may be required for protective and pathological responses in gastrointestinal helminth infection.
    Mucosal Immunol. 2008 Mar;1(2):147-55 PMID: 19079172
  16. Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression.
    Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6955-60 PMID: 23569250
  17. Notch1 expression on T cells is not required for CD4+ T helper differentiation.
    Eur J Immunol. 2004 Jun;34(6):1588-96 PMID: 15162428
  18. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism.
    Immunity. 1998 Nov;9(5):745-55 PMID: 9846495
  19. GATA-3-dependent enhancer activity in IL-4 gene regulation.
    J Immunol. 1998 Oct 15;161(8):3822-6 PMID: 9780146
  20. Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene.
    Immunity. 1995 May;2(5):473-83 PMID: 7749982
  21. Identification of a conserved GATA3 response element upstream proximal from the interleukin-13 gene locus.
    J Biol Chem. 2002 Nov 1;277(44):42399-408 PMID: 12205084
  22. Notch signaling is an important regulator of type 2 immunity.
    J Exp Med. 2005 Oct 17;202(8):1037-42 PMID: 16230473
  23. NIP45 controls the magnitude of the type 2 T helper cell response.
    Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3663-8 PMID: 20133688
  24. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells.
    Nat Immunol. 2011 Jan;12(1):77-85 PMID: 21131966
  25. Responsiveness of naive CD4 T cells to polarizing cytokine determines the ratio of Th1 and Th2 cell differentiation.
    J Immunol. 2006 Feb 1;176(3):1553-60 PMID: 16424184
  26. Stat5 activation plays a critical role in Th2 differentiation.
    Immunity. 2003 Nov;19(5):739-48 PMID: 14614860
  27. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene.
    Nature. 1996 Apr 18;380(6575):630-3 PMID: 8602264
  28. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells.
    Immunity. 1996 Mar;4(3):313-9 PMID: 8624821
  29. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells.
    J Exp Med. 2000 Jul 3;192(1):105-15 PMID: 10880531
  30. Role of NFATx (NFAT4/NFATc3) in expression of immunoregulatory genes in murine peripheral CD4+ T cells.
    J Immunol. 2003 Mar 15;170(6):3109-17 PMID: 12626567
  31. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo.
    Immunity. 2000 Jun;12(6):643-52 PMID: 10894164
  32. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1993-8 PMID: 14769923
  33. Interleukin 2 plays a central role in Th2 differentiation.
    Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3880-5 PMID: 15004274
  34. The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production.
    Immunity. 1998 Jan;8(1):115-24 PMID: 9462517
  35. IL-4 directs the development of Th2-like helper effectors.
    J Immunol. 1990 Dec 1;145(11):3796-806 PMID: 2147202
  36. NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naïve T(H)cells.
    Nat Immunol. 2002 Jan;3(1):48-54 PMID: 11740499
  37. Dynamic changes in histone-methylation 'marks' across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells.
    Nat Immunol. 2007 Jul;8(7):723-31 PMID: 17546034
  38. Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation.
    Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):276-81 PMID: 23248301
  39. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.
    J Immunol. 1986 Apr 1;136(7):2348-57 PMID: 2419430
  40. Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene.
    Immunity. 2002 May;16(5):649-60 PMID: 12049717
  41. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch.
    Immunity. 2007 Jul;27(1):89-99 PMID: 17658279
  42. NFAT1 and NFAT2 are positive regulators of IL-4 gene transcription.
    Eur J Immunol. 2002 Oct;32(10):2971-8 PMID: 12355451
  43. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus.
    Immunity. 2009 Oct 16;31(4):551-64 PMID: 19818655
  44. Friend of GATA-1 represses GATA-3-dependent activity in CD4+ T cells.
    J Exp Med. 2001 Nov 19;194(10):1461-71 PMID: 11714753
  45. Interchromosomal associations between alternatively expressed loci.
    Nature. 2005 Jun 2;435(7042):637-45 PMID: 15880101
  46. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development.
    Immunity. 1998 Nov;9(5):627-35 PMID: 9846484
  47. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells.
    Immunity. 2009 Jan 16;30(1):155-67 PMID: 19144320
  48. Th2 differentiation is unaffected by Jagged2 expression on dendritic cells.
    J Immunol. 2008 Jun 15;180(12):7931-7 PMID: 18523256
  49. Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions.
    Nat Immunol. 2005 Jan;6(1):42-8 PMID: 15608641
  50. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.
    Immunity. 1999 Jun;10(6):745-51 PMID: 10403649
  51. Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction.
    Nat Immunol. 2002 Jul;3(7):652-8 PMID: 12055627
  52. Essential role of Stat6 in IL-4 signalling.
    Nature. 1996 Apr 18;380(6575):627-30 PMID: 8602263
  53. Interaction between GATA-3 and the transcriptional coregulator Pias1 is important for the regulation of Th2 immune responses.
    J Immunol. 2007 Dec 15;179(12):8297-304 PMID: 18056374
  54. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.
    Cell. 1996 Jun 28;85(7):973-83 PMID: 8674125
  55. Molecular analysis of a locus control region in the T helper 2 cytokine gene cluster: a target for STAT6 but not GATA3.
    Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16010-5 PMID: 15507491
  56. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile.
    J Immunol. 2000 Mar 15;164(6):3047-55 PMID: 10706693
  57. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3.
    J Exp Med. 1994 Apr 1;179(4):1285-95 PMID: 7908323
  58. Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation.
    J Biol Chem. 2008 Oct 17;283(42):28216-25 PMID: 18701459
  59. Cutting edge: Identification of an alternative GATA-3 promoter directing tissue-specific gene expression in mouse and human.
    J Immunol. 2002 May 1;168(9):4268-71 PMID: 11970965
  60. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment.
    J Exp Med. 2005 Sep 19;202(6):793-804 PMID: 16172258
  61. GATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels.
    Clin Immunol. 1999 May;91(2):134-44 PMID: 10227805
  62. A 3' enhancer in the IL-4 gene regulates cytokine production by Th2 cells and mast cells.
    Immunity. 2002 Jul;17(1):41-50 PMID: 12150890
  63. NF-kappa B synergizes with NF-AT and NF-IL6 in activation of the IL-4 gene in T cells.
    Eur J Immunol. 2004 Apr;34(4):1111-8 PMID: 15048722
  64. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma.
    Nat Immunol. 2007 Jul;8(7):732-42 PMID: 17546033
  65. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types.
    Immunity. 2011 Aug 26;35(2):299-311 PMID: 21867929
  66. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.
    Cell. 1997 May 16;89(4):587-96 PMID: 9160750
  67. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc.
    Immunity. 1998 Jan;8(1):125-34 PMID: 9462518
  68. Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma.
    Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10614-9 PMID: 20483988
  69. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells.
    Nat Immunol. 2007 Feb;8(2):145-53 PMID: 17195845
  70. T-cell subset regulation in atopy.
    Curr Allergy Asthma Rep. 2011 Apr;11(2):139-45 PMID: 21271314
  71. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites.
    Immunol Rev. 2004 Oct;201:139-55 PMID: 15361238
  72. Friend of GATA is expressed in naive Th cells and functions as a repressor of GATA-3-mediated Th2 cell development.
    J Immunol. 2002 May 1;168(9):4538-45 PMID: 11971000
  73. NF-AT-Driven interleukin-4 transcription potentiated by NIP45.
    Science. 1996 Dec 13;274(5294):1903-5 PMID: 8943202
  74. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma.
    Immunity. 2010 Apr 23;32(4):507-17 PMID: 20399120
  75. Repression of interleukin-4 in T helper type 1 cells by Runx/Cbf beta binding to the Il4 silencer.
    J Exp Med. 2007 Aug 6;204(8):1749-55 PMID: 17646405
  76. Temporal and spatial changes of histone 3 K4 dimethylation at the IFN-gamma gene during Th1 and Th2 cell differentiation.
    J Immunol. 2007 Nov 15;179(10):6410-5 PMID: 17982028
  77. Deletion of a coordinate regulator of type 2 cytokine expression in mice.
    Nat Immunol. 2001 Sep;2(9):842-7 PMID: 11526400
  78. Transcriptional regulation of GATA3 in T helper cells by the integrated activities of transcription factors downstream of the interleukin-4 receptor and T cell receptor.
    J Biol Chem. 2009 Jan 30;284(5):3037-3048 PMID: 19056736
  79. Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster.
    J Immunol. 2000 Dec 15;165(12):6687-91 PMID: 11120785
  80. Up-regulation of Hlx in immature Th cells induces IFN-gamma expression.
    J Immunol. 2004 Jan 1;172(1):114-22 PMID: 14688316
  81. The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression.
    J Exp Med. 2003 Jul 7;198(1):51-61 PMID: 12835475
  82. Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE.
    J Clin Invest. 2006 May;116(5):1327-36 PMID: 16628252
  83. GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rbeta2 chain or T-bet.
    Immunity. 2003 Mar;18(3):415-28 PMID: 12648458
  84. A novel transcription factor, T-bet, directs Th1 lineage commitment.
    Cell. 2000 Mar 17;100(6):655-69 PMID: 10761931
  85. Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region.
    Immunity. 2004 Dec;21(6):865-76 PMID: 15589174
  86. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level.
    Immunity. 2001 Apr;14(4):447-59 PMID: 11336690
  87. MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity.
    Nat Immunol. 2009 Jul;10(7):697-705 PMID: 19465906
  88. Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation.
    J Immunol. 2002 Jul 15;169(2):647-50 PMID: 12097365
  89. Demethylation of a specific hypersensitive site in the Th2 locus control region.
    Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17052-7 PMID: 17940027
  90. Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3.
    J Immunol. 1998 Oct 15;161(8):3817-21 PMID: 9780145
  91. Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition.
    PLoS One. 2008 Jul 30;3(7):e2823 PMID: 18665263
  92. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus.
    Nat Immunol. 2004 Oct;5(10):1017-27 PMID: 15378057
  93. 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. 1992 Oct 1;176(4):1091-8 PMID: 1328464
  94. Basal chromatin modification at the IL-4 gene in helper T cells.
    J Immunol. 2003 Dec 15;171(12):6672-9 PMID: 14662870
  95. Characterization of cis-regulatory elements and nuclear factors conferring Th2-specific expression of the IL-5 gene: a role for a GATA-binding protein.
    J Immunol. 1998 Mar 1;160(5):2343-52 PMID: 9498775
  96. Notch signalling: a simple pathway becomes complex.
    Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89 PMID: 16921404
  97. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells.
    Cell. 2004 May 14;117(4):515-26 PMID: 15137944
  98. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment.
    Immunity. 2000 Jan;12(1):27-37 PMID: 10661403
  99. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses.
    Nat Immunol. 2004 Nov;5(11):1157-65 PMID: 15475959
Article Info
Journal
Immunology
Abbr.
Immunology
ISSN
1365-2567
DOI
10.1111/imm.12121
Email
zengw@marshall.edu
Published
2013-09-00
Pages
31-8
Language
English
Region
England
NLM ID
0374672
PMCID
PMC3809703
Subset
IM
External Links
PubMed source DOI: 10.1111/imm.12121 PMC Full Text View journal details
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