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Transcription factor interplay in T helper cell differentiation

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Evans, C. M., Jenner, R. G.·2013·Briefings in Functional Genomics
DOI 10.1093/bfgp/elt025PMC PMC3838196
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Abstract

The differentiation of CD4 helper T cells into specialized effector lineages has provided a powerful model for understanding immune cell differentiation. Distinct lineages have been defined by differential expression of signature cytokines and the lineage-specifying transcription factors necessary and sufficient for their production. The traditional paradigm of differentiation towards Th1 and Th2 subtypes driven by T-bet and GATA3, respectively, has been extended to incorporate additional T cell lineages and transcriptional regulators. Technological advances have expanded our view of these lineage-specifying transcription factors to the whole genome and revealed unexpected interplay between them. From these data, it is becoming clear that lineage specification is more complex and plastic than previous models might have suggested. Here, we present an overview of the different forms of transcription factor interplay that have been identified and how T cell phenotypes arise as a product of this interplay within complex regulatory networks. We also suggest experimental strategies that will provide further insight into the mechanisms that underlie T cell lineage specification and plasticity.

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  1. [1]Mosmann TR Cherwinski H Bond MW Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins J Immunol 1986 136 2348 57 2419430
  2. [2]Zhu J Yamane H Paul WE Differentiation of Effector CD4 T Cell Populations Annu Rev Immunol 2010 28 445 89 20192806 PMC3502616
  3. [3]Szabo SJ Kim ST Costa GL A novel transcription factor, T-bet, directs Th1 lineage commitment Cell 2000 100 655 69 10761931
  4. [5]Miller SA Weinmann AS Common themes emerge in the transcriptional control of T helper and developmental cell fate decisions regulated by the T-box, GATA and ROR families Immunology 2009 126 306 15 19302139 PMC2669811
  5. [6]Chen W Jin W Hardegen N Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3 J Exp Med 2003 198 1875 86 14676299 PMC2194145
  6. [7]Toda A Piccirillo CA Development and function of naturally occurring CD4+CD25+ regulatory T cells J Leukoc Biol 2006 80 458 70 16809644
  7. [8]Curotto de Lafaille MA Lafaille JJ Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009 30 626 35 19464985
  8. [9]Ivanov II McKenzie BS Zhou L The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells Cell 2006 126 1121 33 16990136
  9. [10]Fontenot JD Gavin MA Rudensky AY Foxp3 programs the development and function of CD4+CD25+ regulatory T cells Nat Immunol 2003 4 330 6 12612578
  10. [11]Hori S Nomura T Sakaguchi S Control of regulatory T cell development by the transcription factor Foxp3 Science 2003 299 1057 61 12522256
  11. [12]Khattri R Cox T Yasayko SA An essential role for Scurfin in CD4+CD25+ T regulatory cells Nat Immunol 2003 4 337 42 12612581
  12. [13]Nurieva RI Chung Y Martinez GJ Bcl6 mediates the development of T follicular helper cells Science 2009 325 1001 5 19628815 PMC2857334
  13. [14]Johnston RJ Poholek AC, DiToro D, et al., Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation Science 2009 325 1006 10 19608860 PMC2766560
  14. [15]Yu D Rao S Tsai LM The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment Immunity 2009 31 457 68 19631565
  15. [16]Kaplan MH Th9 cells: differentiation and disease Immunol Rev 2013 252 104 15 23405898 PMC3982928
  16. [17]Eyerich S Eyerich K Pennino D Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling J Clin Invest 2009 119 3573 85 19920355 PMC2786807
  17. [19]O'Shea JJ Paul WE Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells Science 2010 327 1098 102 20185720 PMC2997673
  18. [20]Nakayamada S Takahashi H Kanno Y Helper T cell diversity and plasticity Curr Opin Immunol 2012 24 297 302 22341735 PMC3383341
  19. [21]Hegazy AN Peine M Helmstetter C Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions Immunity 2010 32 116 28 20079668
  20. [22]Wang Y Su MA Wan YY An essential role of the transcription factor GATA-3 for the function of regulatory T cells Immunity 2011 35 337 48 21924928 PMC3182399
  21. [23]Wohlfert EA Grainger JR Bouladoux N GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice J Clin Invest 2011 121 4503 15 21965331 PMC3204837
  22. [24]Rudra D deRoos P Chaudhry A Transcription factor Foxp3 and its protein partners form a complex regulatory network Nat Immunol 2012 13 1010 9 22922362 PMC3448012
  23. [25]Koch MA Tucker-Heard G Perdue NR The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation Nat Immunol 2009 10 595 602 19412181 PMC2712126
  24. [26]Stock P Akbari O Berry G Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity Nat Immunol 2004 5 1149 56 15448689
  25. [27]Oldenhove G Bouladoux N Wohlfert EA Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection Immunity 2009 31 772 86 19896394 PMC2814877
  26. [28]Hall AO Beiting DP, Tato C, et al., The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology Immunity 2012 37 511 23 22981537 PMC3477519
  27. [29]Ichiyama K Yoshida H Wakabayashi Y Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat J Biol Chem 2008 283 17003 8 18434325
  28. [30]Zhou L Lopes JE Chong MM TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function Nature 2008 453 236 40 18368049 PMC2597437
  29. [31]Lochner M Peduto L Cherrier M In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells J Exp Med 2008 205 1381 93 18504307 PMC2413035
  30. [32]Tartar DM VanMorlan AM Wan X FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes J Immunol 2010 184 3377 85 20181889 PMC2843758
  31. [33]Linterman MA Pierson W Lee SK Foxp3+ follicular regulatory T cells control the germinal center response Nat Med 2011 17 975 82 21785433 PMC3182542
  32. [34]Chung Y Tanaka S, Chu F, et al., Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions Nat Med 2011 17 983 8 21785430 PMC3151340
  33. [35]Nakayamada S Kanno Y Takahashi H Early Th1 cell differentiation is marked by a Tfh cell-like transition Immunity 2011 35 919 31 22195747 PMC3244883
  34. [36]Pepper M Pagan AJ Igyarto BZ Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells Immunity 2011 35 583 95 22018468 PMC3208313
  35. [37]Oestreich KJ Huang AC Weinmann AS The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns J Exp Med 2011 208 1001 13 21518797 PMC3092354
  36. [38]Oestreich KJ Mohn SE Weinmann AS Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile Nat Immunol 2012 13 405 11 22406686 PMC3561768
  37. [39]Cousins DJ Lee TH, Staynov DZ., Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2 cytokines J Immunol 2002 169 2498 506 12193719
  38. [40]Jenner RG Townsend MJ Jackson I The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes Proc Natl Acad Sci USA 2009 106 17876 81 19805038 PMC2764903
  39. [42]Messi M Giacchetto I Nagata K Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes Nat Immunol 2003 4 1 78 86 12447360
  40. [43]Acosta-Rodriguez EV Rivino L Geginat J Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells Nat Immunol 2007 8 639 46 17486092
  41. [44]Ghoreschi K Laurence A Yang XP Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling Nature 2010 467 967 71 20962846 PMC3108066
  42. [45]Nistala K Adams S Cambrook H Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment Proc Natl Acad Sci USA 2010 107 14751 6 20679229 PMC2930428
  43. [47]Lee Y Awasthi A Yosef N Induction and molecular signature of pathogenic TH17 cells Nat Immunol 2012 13 991 9 22961052 PMC3459594
  44. [48]Wang YH Voo KS Liu B A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma J Exp Med 2010 207 2479 91 20921287 PMC2964570
  45. [49]Thierfelder WE van Deursen JM, Yamamoto K, et al., Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells Nature 1996 382 171 4 8700208
  46. [50]Afkarian M Sedy JR Yang J T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells Nat Immunol 2002 3 549 57 12006974
  47. [51]Kaplan MH Schindler U, Smiley ST, et al., Stat6 is required for mediating responses to IL-4 and for development of Th2 cells Immunity 1996 4 313 9 8624821
  48. [52]Yang XO Panopoulos AD Nurieva R STAT3 regulates cytokine-mediated generation of inflammatory helper T cells J Biol Chem 2007 282 9358 63 17277312
  49. [53]Burchill MA Yang J Vogtenhuber C IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells J Immunol 2007 178 280 90 17182565
  50. [54]Wei L Vahedi G Sun HW Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation Immunity 2010 32 840 51 20620946 PMC2904651
  51. [55]Vahedi G Takahashi H Nakayamada S STATs shape the active enhancer landscape of T cell populations Cell 2012 151 981 93 23178119 PMC3509201
  52. [56]Ciofani M Madar A Galan C A validated regulatory network for Th17 cell specification Cell 2012 151 289 303 23021777 PMC3503487
  53. [58]Lu B Zagouras P Fischer JE Kinetic analysis of genomewide gene expression reveals molecule circuitries that control T cell activation and Th1/2 differentiation Proc Natl Acad Sci USA 2004 101 3023 8 14978277 PMC365738
  54. [59]Lund RJ Loytomaki M Naumanen T Genome-wide identification of novel genes involved in early Th1 and Th2 cell differentiation J Immunol 2007 178 3648 60 17339462
  55. [61]Zhu J Cote-Sierra J Guo L Stat5 activation plays a critical role in Th2 differentiation Immunity 2003 19 739 48 14614860
  56. [62]Cote-Sierra J Foucras G Guo L Interleukin 2 plays a central role in Th2 differentiation Proc Natl Acad Sci USA 2004 101 3880 5 15004274 PMC374338
  57. [63]Liao W Schones DE Oh J Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression Nat Immunol 2008 9 1288 96 18820682 PMC2762127
  58. [64]Takatori H Nakajima H Hirose K Indispensable role of Stat5a in Stat6-independent Th2 cell differentiation and allergic airway inflammation J Immunol 2005 174 3734 40 15749913
  59. [65]Elo LL Jarvenpaa H Tuomela S Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming Immunity 2010 32 852 62 20620947
  60. [66]Yang XP Ghoreschi K Steward-Tharp SM Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5 Nat Immunol 2011 12 247 54 21278738 PMC3182404
  61. [67]Stritesky GL Muthukrishnan R Sehra S The transcription factor STAT3 is required for T helper 2 cell development Immunity 2011 34 39 49 21215659 PMC3040244
  62. [68]Grenningloh R Kang BY Ho IC Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses J Exp Med 2005 201 615 26 15728239 PMC2213045
  63. [69]Mullen AC Hutchins AS High FA Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction Nat Immunol 2002 3 652 8 12055627
  64. [70]Djuretic IM Levanon D Negreanu V Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells Nat Immunol 2007 8 145 53 17195845
  65. [71]Shinnakasu R Yamashita M Kuwahara M Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation J Biol Chem 2008 283 28216 25 18701459 PMC2661392
  66. [72]Tanaka Y So T Lebedeva S Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice Blood 2005 106 1286 95 15845902 PMC1895205
  67. [73]Ouyang W Lohning M Gao Z Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment Immunity 2000 12 27 37 10661403
  68. [74]Yang XO Angkasekwinai P Zhu J Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment Nat Immunol 2009 10 1260 6 19881507 PMC2784129
  69. [75]Zhang F Meng G Strober W Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells Nat Immunol 2008 9 1297 306 18849990 PMC4778724
  70. [76]Schraml BU Hildner K Ise W The AP-1 transcription factor Batf controls T(H)17 differentiation Nature 2009 460 405 9 19578362 PMC2716014
  71. [77]Fu W Ergun A Lu T A multiply redundant genetic switch ‘locks in' the transcriptional signature of regulatory T cells Nat Immunol 2012 13 972 80 22961053 PMC3698954
  72. [79]Oestreich KJ Weinmann AS Master regulators or lineage-specifying? Changing views on CD4+ T cell transcription factors Nat Rev Immunol 2012 12 799 804 23059426 PMC3584691
  73. [80]Sundrud MS Nolan MA Synergistic and combinatorial control of T cell activation and differentiation by transcription factors Curr Opin Immunol 2010 22 286 92 20399089
  74. [81]Ono M Yaguchi H Ohkura N Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1 Nature 2007 446 685 9 17377532
  75. [82]Klunker S Chong MM Mantel PY Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells J Exp Med 2009 206 2701 15 19917773 PMC2806624
  76. [83]Yang L Anderson DE Baecher-Allan C IL-21 and TGF-beta are required for differentiation of human T(H)17 cells Nature 2008 454 350 2 18469800 PMC2760130
  77. [84]Yang Y Weiner J Liu Y T-bet is essential for encephalitogenicity of both Th1 and Th17 cells J Exp Med 2009 206 1549 64 19546248 PMC2715092
  78. [85]De Fanis U Mori F Kurnat RJ GATA3 up-regulation associated with surface expression of CD294/CRTH2: a unique feature of human Th cells Blood 2007 109 4343 50 17234745 PMC1885489
  79. [86]Usui T Preiss JC Kanno Y T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription J Exp Med 2006 203 3 755 66 16520391 PMC2118252
  80. [88]Hwang ES Szabo SJ Schwartzberg PL T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3 Science 2005 307 430 3 15662016
  81. [89]Kohu K Ohmori H Wong WF The Runx3 transcription factor augments Th1 and down-modulates Th2 phenotypes by interacting with and attenuating GATA3 J Immunol 2009 183 7817 24 19933870
  82. [90]Yagi R Junttila IS Wei G The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma Immunity 2010 32 507 17 20399120 PMC2867662
  83. [91]Garg V Kathiriya IS Barnes R GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 Nature 2003 424 443 7 12845333
  84. [92]Wei G Abraham BJ Yagi R Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types Immunity 2011 35 299 311 21867929 PMC3169184
  85. [94]Kouros-Mehr H Kim JW Bechis SK GATA-3 and the regulation of the mammary luminal cell fate Curr Opin Cell Biol 2008 20 164 70 18358709 PMC2397451
  86. [95]Triulzi T Tagliabue E Balsari A FOXP3 expression in tumor cells and implications for cancer progression J Cell Physiol 2013 228 30 5 22674548
  87. [96]Polonsky M Zaretsky I Friedman N Dynamic single-cell measurements of gene expression in primary lymphocytes: challenges, tools and prospects Brief Funct Genomics 2013 12 99 108 23334501

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Authors
Evans, C. M., & Jenner, R. G.
Affiliations
University College London (GB)
Corresponding author
Jenner, R. G.
ORCID
Venue
Briefings in Functional Genomics
Publisher
Oxford University Press (OUP)
Published
2013-07-22
Volume
12
Issue
6
Pages
499-511
ISSN
  • 2041-2647 (ISSN-L)
  • 2041-2649
  • 2041-2657
DOI
10.1093/bfgp/elt025
PMC
PMC3838196
OpenAlex
W2161767894
Cited by
91
References
9
Citations by year
2026: 2 · 2025: 3 · 2024: 11 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 5 · 2013: 2
FWCI
0.67
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Briefings in Functional Genomics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Wellcome Trust (091009)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
T helper cell differentiation, transcription factors, T cell lineage specification, Th1 cells, Th2 cells, T-bet, GATA3, transcriptional regulatory networks, T cell plasticity, CD4+ T cells
MeSH terms
Animals, Cell Differentiation, T-Lymphocytes, Helper-Inducer, Humans, Transcription Factors

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