Transcriptional regulators dictate innate lymphoid cell fates

Abstract

Research on innate lymphoid cells (ILC) has recently been a fast paced topic of immunological research. As ILCs are able to produce signature Th cytokine, ILCs have garnered considerable attention and have been described to represent the innate counterpart of the CD4⁺ T helper (Th) cells. The development and function of ILCs are precisely regulated by a network of crucial transcription factors, which are also involved in the development or differentiation of conventional natural killer (cNK) cells and T cells. In this review, we will summarize the key transcriptional regulators and their functions through each phases of ILC development. With the phase of ILC lineage commitment, we will focus in particular on the roles of the transcription regulators Id2 and GATA-3, which in collaboration with other transcriptional factors, are critically involved in the generation of ILC fate determined progenitors. Once an ILC lineage has been established, several other transcription factors are required for the specification and functional regulation of distinct mature ILC subsets. Thus, a comprehensive understanding of the interactions and regulatory mechanisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.

Key words： innate lymphoid cell; transcription factors; GATA-3; Id2

References

1 AliahmadP, KayeJ (2008) Development of all CD4 T lineages requires nuclear factor TOX. J Exp Med205:245–256

2 AliahmadP, de la TorreB, KayeJ (2010) Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat Immunol11:945–952

3 ArtisD, SpitsH (2015) The biology of innate lymphoid cells. Nature517:293–301

4 BandoJK, LiangHE, LocksleyRM (2015) Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat Immunol16:153–160

5 BjorklundAK, ForkelM, PicelliS, KonyaV, TheorellJ, FribergD, SandbergR, MjosbergJ(2016) The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol17:451–460

6 BoosMD, YokotaY, EberlG, KeeBL (2007) Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med204:1119–1130

7 BrubakerSW, BonhamKS, ZanoniI, KaganJC (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol33:257–290

8 CalifanoD, ChoJJ, UddinMN, LorentsenKJ, YangQ, BhandoolaA, LiH, AvramD (2015) Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity43:354–368

9 CellaM, FuchsA, VermiW, FacchettiF, OteroK, LennerzJK, DohertyJM, MillsJC, ColonnaM (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature457:722–725

10 CheaS, SchmutzS, BerthaultC, PerchetT, PetitM, Burlen-DefranouxO, GoldrathAW, RodewaldHR, CumanoA, GolubR(2016) Single-cell gene expression analyses reveal heterogeneous responsiveness of fetal innate lymphoid progenitors to notch signaling. Cell Rep14:1500–1516

11 ConstantinidesMG, McDonaldBD, VerhoefPA, BendelacA (2014) A committed precursor to innate lymphoid cells. Nature508:397–401

12 ConstantinidesMG, GudjonsonH, McDonaldBD, IshizukaIE, VerhoefPA, DinnerAR, BendelacA (2015) PLZF expression maps the early stages of ILC1 lineage development. Proc Natl Acad Sci USA112:5123–5128

13 DaussyC, FaureF, MayolK, VielS, GasteigerG, CharrierE, BienvenuJ, HenryT, DebienE, HasanUA (2014) T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med211:563–577

14 DudakovJA, HanashAM, van den BrinkMR (2015) Interleukin-22: immunobiology and pathology. Annu Rev Immunol33:747–785

15 EberlG, ColonnaM, Di SantoJP, McKenzieAN (2015a) Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science348:aaa6566

16 EberlG, Di SantoJP, VivierE (2015b) The brave new world of innate lymphoid cells. Nat Immunol16:1–5

17 EbiharaT, SongC, RyuSH, Plougastel-DouglasB, YangL, LevanonD, GronerY, BernMD, StappenbeckTS, ColonnaM (2015) Runx3 specifies lineage commitment of innate lymphoid cells. Nat Immunol16:1124–1133

18 FallonPG, BallantyneSJ, ManganNE, BarlowJL, DasvarmaA, HewettDR, McIlgormA, JolinHE, McKenzieAN (2006) Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med203:1105–1116

19 FinkeD (2005) Fate and function of lymphoid tissue inducer cells. Curr Opin Immunol17:144–150

20 GascoyneDM, LongE, Veiga-FernandesH, de BoerJ, WilliamsO, SeddonB, ColesM, KioussisD, BradyHJ (2009) The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat Immunol10:1118–1124

21 GasteigerG, FanX, DikiyS, LeeSY, RudenskyAY (2015) Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science350:981–985

22 GermainRN (2002) T-cell development and the CD4−CD8 lineage decision. Nat Rev Immunol2:309–322

23 GordonSM, ChaixJ, RuppLJ, WuJ, MaderaS, SunJC, LindstenT, ReinerSL (2012) The transcription factors T-bet and Eomes control key checkpoints of natural killer cellmaturation. Immunity36:55–67

24 GotoY, ObataT, KunisawaJ, SatoS, IvanovII, LamichhaneA, TakeyamaN, KamiokaM, SakamotoM, MatsukiT (2014) Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science345:1254009

25 Gury-BenAriM, ThaissCA, SerafiniN, WinterDR, GiladiA, Lara-AstiasoD, LevyM, SalameTM, WeinerA, DavidE (2016) The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell166(1231–1246):e1213

26 HalimTY, MacLarenA, RomanishMT, GoldMJ, McNagnyKM, TakeiF (2012) Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity37:463–474

27 HalimTY, SteerCA, MathaL, GoldMJ, Martinez-GonzalezI, McNagnyKM, McKenzieAN, TakeiF (2014) Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity40:425–435

28 HalimTY, HwangYY, ScanlonST, ZaghouaniH, GarbiN, FallonPG, McKenzieAN (2016) Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat Immunol17:57–64

29 HanashAM, DudakovJA, HuaG, O’ConnorMH, YoungLF, SingerNV, WestML, JenqRR, HollandAM, KappelLW (2012) Interleukin-22 protects intestinal stem cells from immunemediated tissue damage and regulates sensitivity to graft versus host disease. Immunity37:339–350

30 HepworthMR, MonticelliLA, FungTC, ZieglerCG, GrunbergS, SinhaR, MantegazzaAR, MaHL, CrawfordA, AngelosantoJM (2013) Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature498:113–117

31 HepworthMR, FungTC, MasurSH, KelsenJR, McConnellFM, DubrotJ, WithersDR, HuguesS, FarrarMA, ReithW (2015) Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4(+) T cells. Science348:1031–1035

32 HoIC, TaiTS, PaiSY (2009) GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol9:125–135

33 HoylerT, KloseCS, SouabniA, Turqueti-NevesA, PfeiferD, RawlinsEL, VoehringerD, BusslingerM, DiefenbachA (2012) The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity37:634–648

34 IkawaT, HiroseS, MasudaK, KakugawaK, SatohR, Shibano-SatohA, KominamiR, KatsuraY, KawamotoH (2010) An essential developmental checkpoint for production of the T cell lineage. Science329:93–96

35 IshizukaIE, CheaS, GudjonsonH, ConstantinidesMG, DinnerAR, BendelacA, GolubR (2016) Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat Immunol17:269–276

36 KeeBL (2009) E and ID proteins branch out. Nat Rev Immunol9:175–184

37 KimMH, TaparowskyEJ, KimCH (2015) Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity43:107–119

38 KissEA, VonarbourgC, KopfmannS, HobeikaE, FinkeD, EsserC, DiefenbachA (2011) Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science334:1561–1565

39 KloseCS, KissEA, SchwierzeckV, EbertK, HoylerT, d’HarguesY, GoppertN, CroxfordAL, WaismanA, TanriverY, DiefenbachA (2013) A T-bet gradient controls the fate and function of CCR6-RORgammat+ innate lymphoid cells. Nature494:261–265

40 KloseCS, FlachM, MohleL, RogellL, HoylerT, EbertK, FabiunkeC, PfeiferD, SexlV, Fonseca-PereiraD (2014) Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell157:340–356

41 LeeJS, CellaM, McDonaldKG, GarlandaC, KennedyGD, NukayaM, MantovaniA, KopanR, BradfieldCA, NewberryRD, ColonnaM (2011) AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol13:144–151

42 LeeMW, OdegaardJI, MukundanL, QiuY, MolofskyAB, NussbaumJC, YunK, LocksleyRM, ChawlaA (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell160:74–87

43 LiS, HellerJJ, BostickJW, LeeA, SchjervenH, KastnerP, ChanS, ChenZE, ZhouL (2016) Ikaros inhibits group 3 innate lymphoid cell development and function by suppressing the aryl hydrocarbon receptor pathway. Immunity45:185–197

44 LindemansCA, CalafioreM, MertelsmannAM, O’ConnorMH, DudakovJA, JenqRR, VelardiE, YoungLF, SmithOM, LawrenceG (2015) Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature528:560–564

45 LoBC, GoldMJ, HughesMR, AntignanoF, ValdezY, ZaphC, HarderKW, McNagnyKM (2016) The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease. Sci Immunol1(3):aaf8864

46 LuciC, ReyndersA, IvanovII, CognetC, ChicheL, ChassonL, HardwigsenJ, AnguianoE, BanchereauJ, ChaussabelD (2009) Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol10:75–82

47 MielkeLA, GroomJR, RankinLC, SeilletC, MassonF, PutoczkiT, BelzGT (2013a) TCF-1 controls ILC2 and NKp46+RORgammat+ innate lymphocyte differentiation and protection in intestinal inflammation. J Immunol191:4383–4391

48 MielkeLA,JonesSA, RaverdeauM, HiggsR, StefanskaA, GroomJR, MisiakA, DunganLS, SuttonCE, StreubelG (2013b) Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med210:1117–1124

49 MonticelliLA, SonnenbergGF, AbtMC, AlenghatT, ZieglerCG, DoeringTA, AngelosantoJM, LaidlawBJ, YangCY, SathaliyawalaT (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol12:1045–1054

50 MoroK, YamadaT, TanabeM, TakeuchiT, IkawaT, KawamotoH, FurusawaJ, OhtaniM, FujiiH, KoyasuS (2010) Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature463:540–544

51 NeillDR, WongSH, BellosiA, FlynnRJ, DalyM, LangfordTK, BucksC, KaneCM, FallonPG, PannellR (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature464:1367–1370

52 NussbaumJC, Van DykenSJ, von MoltkeJ, ChengLE, MohapatraA, MolofskyAB, ThorntonEE, KrummelMF, ChawlaA, LiangHE, LocksleyRM (2013) Type 2 innate lymphoid cells control eosinophil homeostasis. Nature502:245–248

53 OliphantCJ, HwangYY, WalkerJA, SalimiM, WongSH, BrewerJM, EnglezakisA, BarlowJL, HamsE, ScanlonST (2014) MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity41:283–295

54 O’SheaJJ, PaulWE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science327:1098–1102

55 PaiSY, TruittML, TingCN, LeidenJM, GlimcherLH, HoIC (2003) Critical roles for transcription factor GATA-3 in thymocyte development. Immunity19:863–875

56 PantelyushinS, HaakS, IngoldB, KuligP, HeppnerFL, NavariniAA, BecherB (2012) Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice. J Clin Invest122:2252–2256

57 PickardJM, MauriceCF, KinnebrewMA, AbtMC, SchentenD, GolovkinaTV, BogatyrevSR, IsmagilovRF, PamerEG, TurnbaughPJ, ChervonskyAV (2014) Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature514:638–641

58 PossotC, SchmutzS, CheaS, BoucontetL, LouiseA, CumanoA, GolubR (2011) Notch signaling is necessary for adult, but not fetal, development of RORgammat(+) innate lymphoid cells. Nat Immunol12:949–958

59 PriceAE, LiangHE, SullivanBM, ReinhardtRL, EisleyCJ, ErleDJ, LocksleyRM (2010) Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A107:11489–11494

60 QiuJ, HellerJJ, GuoX, ChenZM, FishK, FuYX, ZhouL (2012) The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity36:92–104

61 RadtkeF, MacDonaldHR, Tacchini-CottierF (2013) Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol13:427–437

62 SaenzSA, SiracusaMC, MonticelliLA, ZieglerCG, KimBS, BrestoffJR, PetersonLW, WherryEJ, GoldrathAW, BhandoolaA, ArtisD (2013) IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells. J Exp Med210:1823–1837

63 SamsonSI, RichardO, TavianM, RansonT, VosshenrichCA, ColucciF, BuerJ, GrosveldF, GodinI, Di SantoJP (2003) GATA-3 promotes maturation, IFN-gamma production, and liver-specific homing of NK cells. Immunity19:701–711

64 SanosSL, BuiVL, MorthaA, OberleK, HenersC, JohnerC, DiefenbachA (2009) RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol10:83–91

65 SchjervenH, McLaughlinJ, ArenzanaTL, FrietzeS, ChengD, WadsworthSE, LawsonGW, BensingerSJ, FarnhamPJ, WitteON, SmaleST (2013) Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nat Immunol14:1073–1083

66 SciumeG, HiraharaK, TakahashiH, LaurenceA, VillarinoAV, SingletonKL, SpencerSP, WilhelmC, PoholekAC, VahediG (2012) Distinct requirements for T-bet in gut innate lymphoid cells. J Exp Med209:2331–2338

67 SeehusCR, AliahmadP, de la TorreB, IlievID, SpurkaL, FunariVA, KayeJ (2015) The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nat Immunol16:599–608

68 SeilletC, RankinLC, GroomJR, MielkeLA, TellierJ, ChopinM, HuntingtonND, BelzGT, CarottaS (2014) Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med211:1733–1740

69 SerafiniN, Klein WolterinkRG, Satoh-TakayamaN, XuW, VosshenrichCA, HendriksRW, Di SantoJP (2014) Gata3 drives development of RORgammat+ group 3 innate lymphoid cells. J Exp Med211:199–208

70 SojkaDK, Plougastel-DouglasB, YangL, Pak-WittelMA, ArtyomovMN, IvanovaY, ZhongC, ChaseJM, RothmanPB, YuJ (2014) Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife3:e01659

71 SpoonerCJ, LeschJ, YanD, KhanAA, AbbasA, Ramirez-CarrozziV, ZhouM, SorianoR, Eastham-AndersonJ, DiehlL (2013) Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat Immunol14:1229–1236

72 SteinkeFC, YuS, ZhouX, HeB, YangW, ZhouB, KawamotoH, ZhuJ, TanK, XueHH (2014) TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4(+) T cell fate and interact with Runx3 to silence Cd4 in CD8(+) T cells. Nat Immunol15:646–656

73 TachibanaM, TennoM, TezukaC, SugiyamaM, YoshidaH, TaniuchiI (2011) Runx1/Cbfbeta2 complexes are required for lymphoid tissue inducer cell differentiation at two developmental stages. J Immunol186:1450–1457

74 TaghonT, YuiMA, RothenbergEV (2007) Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat Immunol8:845–855

75 TakatoriH, KannoY, WatfordWT, TatoCM, WeissG, IvanovII, LittmanDR, O’SheaJJ (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med206:35–41

76 van de PavertSA, FerreiraM, DominguesRG, RibeiroH, MolenaarR, Moreira-SantosL, AlmeidaFF, IbizaS, BarbosaI, GoverseG (2014) Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature508:123–127

77 Van DykenSJ, NussbaumJC, LeeJ, MolofskyAB, LiangHE, PollackJL, GateRE, HaliburtonGE, YeCJ, MarsonA (2016) A tissue checkpoint regulates type 2 immunity. Nat Immunol17:1381–1387

78 VerykokakisM, ZookEC, KeeBL (2014) ID’ing innate and innatelike lymphoid cells. Immunol Rev261:177–197

79 WalkerJA, OliphantCJ, EnglezakisA, YuY, ClareS, RodewaldHR, BelzGP, LiuPG, FallonAN, McKenzie(2015) Bcl11b is essential for group 2 innate lymphoid cell development. J Exp Med212:875–882

80 WangL, WildtKF, ZhuJ, ZhangX, FeigenbaumL, TessarolloL, PaulWE, FowlkesBJ, BosselutR (2008) Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4(+) T cells. Nat Immunol9:1122–1130

81 WeberBN, ChiAW, ChavezA, Yashiro-OhtaniY, YangQ, ShestovaO, BhandoolaA (2011) A critical role for TCF-1 in T-lineage specification and differentiation. Nature476:63–68

82 WilhelmC, HirotaK, StieglitzB, Van SnickJ, TolainiM, LahlK, SparwasserT, HelmbyH, StockingerB (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol12:1071–1077

83 WongSH, WalkerJA, JolinHE, DrynanLF, HamsE, CameloA, BarlowJL, NeillDR, PanovaV, KochU(2012) Transcription factor RORalpha is critical for nuocyte development. Nat Immunol13:229–236

84 WoolfE, XiaoC, FainaruO, LotemJ, RosenD, NegreanuV, BernsteinY, GoldenbergD, BrennerO, BerkeG (2003)Runx3 and Runx1 are required for CD8 Tcell development during thymopoiesis. Proc Natl Acad Sci USA100:7731–7736

85 XuW, DominguesRG, Fonseca-PereiraD, FerreiraM, RibeiroH, Lopez-LastraS, MotomuraY, Moreira-SantosL, BihlF, BraudV (2015) NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep10:2043–2054

86 YagiR, ZhongC, NorthrupDL, YuF, BouladouxN, SpencerS, HuG, BarronL, SharmaS, NakayamaT (2014) The transcription factor GATA3 is critical for the development of all IL-7Ralphaexpressing innate lymphoid cells. Immunity40:378–388

87 YangQ, MonticelliLA, SaenzSA, ChiAW, SonnenbergGF, TangJ, De ObaldiaME, BailisW, BrysonJL, ToscanoK (2013) Tcell factor 1 is required for group 2 innate lymphoid cell generation. Immunity38:694–704

88 YangQ, LiF, HarlyC, XingS, YeL, XiaX, WangH, WangX, YuS, ZhouX (2015) TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol16:1044–1050

89 YokotaY, MansouriA, MoriS, SugawaraS, AdachiS, NishikawaS, GrussP (1999) Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature397:702–706

90 YoshidaT, NgSY, GeorgopoulosK(2010) Awakening lineage potential by Ikaros-mediated transcriptional priming. Curr Opin Immunol22:154–160

91 YuX, WangY, DengM, LiY, RuhnKA, ZhangCC, HooperLV (2014) The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. Elife3: e04406

92 YuY, WangC, ClareS, WangJ, LeeSC, BrandtC, BurkeS, LuL, HeD, JenkinsNA (2015) The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J Exp Med212:865–874

93 YuY, TsangJC, WangC, ClareS, WangJ, ChenX, BrandtC, KaneL, CamposLS, LuL (2016) Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway. Nature539:102–106

94 YuiMA, RothenbergEV (2014) Developmental gene networks: a triathlon on the course to Tcell identity. Nat Rev Immunol14:529–545

95 ZhongC, ZhuJ (2015a) Bcl11b drives the birth of ILC2 innate lymphocytes. J Exp Med212:828

96 ZhongC, ZhuJ (2015b) Transcriptional regulatory network for the development of innate lymphoid cells. Mediat Inflamm2015:264502

97 ZhongC, CuiK, WilhelmC, HuG, MaoK, BelkaidY, ZhaoK, ZhuJ (2016) Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat Immunol17:169–178

98 ZhouL (2016) AHR Function in Lymphocytes: Emerging Concepts. Trends Immunol37:17–31

99 ZhuJ,GuoL, MinB, WatsonCJ, Hu-LiJ, YoungHA, TsichlisPN, PaulWE (2002) Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. Immunity16:733–744

100 ZhuJ, JankovicD, GrinbergA, GuoL, PaulWE (2006) Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc Natl Acad Sci USA103:18214–18219

101 ZookEC, KeeBL (2016) Development of innate lymphoid cells. Nat Immunol17:775–782

102 ZookEC, RamirezK, GuoX, van der VoortG, SigvardssonM, SvenssonEC, FuYX, KeeBL (2016) The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2. J Exp Med213:687–696