医学免疫学课件：固有免疫细胞发育过程的转录调控

1、The Transcriptional Regulation of Innate Lymphoid Cell Development OUTLINE01BackgroundA Brief Introduction of the Innate Lymphoid Cells 02Transcriptional Regulation of ILC developmentOverview of development scheme, important Transcription factors regulating ILC development03Clinical implicationsPoss

2、ible involvement of ILCs in health and disease04Future DirectionsRecent advances, questions to be solvedThe Transcriptional Regulation of Innate Lymphoid Cell Development01BackgroundA Brief Introduction of the Innate Lymphoid CellsThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentPAR

3、T IBackgroundInnate immune system provides a fast and effective response to common invadersComplement SystemImmune cellsPhagocytes(Macrophages, Neutrophils, Dendritic cells)Basophils & eosinophilsNatural killer cellsMast cells T cells Sompayrac L. How the Immune System Works. UK: WILEY Blackwell; 20

4、16.The Transcriptional Regulation of Innate Lymphoid Cell DevelopmentPART IBackgroundNo recombination activating gene(RAG)-dependent rearranged antigen receptorsLack of myeloid cell and dendritic cell phenotypical markersLymphoid morphologyAlmeida FF, Belz GT. Innate lymphoid cells: models of plasti

5、city for immune homeostasis and rapid responsiveness in protection. Mucosal Immunol 2016;9:1103-12.Defining features of innate lymphoid cells(ILCs)nILC2: natural ILC2siILC2: inflammatory ILC2The Transcriptional Regulation of Innate Lymphoid Cell DevelopmentPART IBackgroundSpits H, Artis D, Colonna M

6、, et al. Innate lymphoid cells-a proposal for uniform nomenclature. Nat Rev Immunol 2013;13:145-9.ILC subsets with diverse phenotypical markers are identifiedTable 1 Phenotypical markers of human ILC subsets The Transcriptional Regulation of Innate Lymphoid Cell DevelopmentPART IBackgroundWalker JA,

7、 Barlow JL, McKenzie AN. Innate lymphoid cells-how did we miss them? Nat Rev Immunol 2013;13:75-87.Classification based on phenotypical and functional characteristicsGroup 1(IFN-)NK cell CD8+ T cellILC1sCD4+ Th1 cellGroup 2(Type 2 cytokines, GATA3, ROR)ILC2s CD4+ Th2 cellGroup 3(RORt, IL-17 and/or I

8、L-22) CD4+ Th17&22 cellLTi(Lymphoid-tissue-inducer)NCR+ & NCR- ILC3sThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentPART IBackgroundWalker JA, Barlow JL, McKenzie AN. Innate lymphoid cells-how did we miss them? Nat Rev Immunol 2013;13:75-87.Summary of ILC subsets, functions and dis

9、ease associationsThe Transcriptional Regulation of Innate Lymphoid Cell Development02Transcriptional Regulation of ILC developmentOverview of development scheme, important Transcription factors regulating ILC developmentThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentPART IITranscr

10、iptional Regulation of ILC developmentSerafini N, Vosshenrich CA, Di Santo JP. Transcriptional regulation of innate lymphoid cell fate. Nat Rev Immunol 2015;15:415-28.ILC development is considered to have three main stagesStage 1: generation of CILCPsCILCPs: common innate lymphoid cell precursors St

11、age 2: diversification of three main ILC groupsStage 3: ILC homeostasis in tissuesThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev I

12、mmunol 2016;34:299-316.Identification of lymphoid-restricted precursors for innate or adaptive immunityCLP: Common Lymphoid PrecursorLP: 47-expressing Lymphoid PrecursorEILP: Early Innate Lymphoid ProgenitorCHILP: Common Helper Innate Lymphoid ProgenitorILCP: Innate Lymphoid Cell ProgenitorPART IITh

13、e Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.Identification of lymphoid-restricted precursors for innate o

14、r adaptive immunityCLP: Common Lymphoid PrecursorLP: 47-expressing Lymphoid PrecursorEILP: Early Innate Lymphoid ProgenitorCHILP: Common Helper Innate Lymphoid ProgenitorILCP: Innate Lymphoid Cell ProgenitorPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (S

15、tage 1: generation of CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.Identification of lymphoid-restricted precursors for innate or adaptive immunityCLP: Common Lymphoid PrecursorLP: 47-expressing Lymphoid Precurso

16、rEILP: Early Innate Lymphoid ProgenitorCHILP: Common Helper Innate Lymphoid ProgenitorILCP: Innate Lymphoid Cell ProgenitorPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A

17、. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.Identification of lymphoid-restricted precursors for innate or adaptive immunityCLP: Common Lymphoid PrecursorLP: 47-expressing Lymphoid PrecursorEILP: Early Innate Lymphoid ProgenitorCHILP: Common Helper Innate Lymphoid Progenit

18、orILCP: Innate Lymphoid Cell ProgenitorPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.Identificatio

19、n of lymphoid-restricted precursors for innate or adaptive immunityCLP: Common Lymphoid PrecursorLP: 47-expressing Lymphoid PrecursorEILP: Early Innate Lymphoid ProgenitorCHILP: Common Helper Innate Lymphoid ProgenitorILCP: Innate Lymphoid Cell ProgenitorPART IIThe Transcriptional Regulation of Inna

20、te Lymphoid Cell DevelopmentTransient PLZF+Developing Scheme (Stage 1: generation of CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.Identification of lymphoid-restricted precursors for innate or adaptive immunityCL

21、P: Common Lymphoid PrecursorLP: 47-expressing Lymphoid PrecursorEILP: Early Innate Lymphoid ProgenitorCHILP: Common Helper Innate Lymphoid ProgenitorILCP: Innate Lymphoid Cell ProgenitorPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of

22、 CILCPs)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.Identification of lymphoid-restricted precursors for innate or adaptive immunityCLP: Common Lymphoid PrecursorLP: 47-expressing Lymphoid PrecursorEILP: Early Innate L

23、ymphoid ProgenitorCHILP: Common Helper Innate Lymphoid ProgenitorILCP: Innate Lymphoid Cell ProgenitorPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of CILCPs)Yang Q, Li F, Harly C, et al. TCF-1 upregulation identifies early innate lym

24、phoid progenitors in the bone marrow. Nat Immunol 2015;16:1044-50.TCF-1 up-regulation identify EILPs in bone marrowTCF-1: T cell factor 1(encoded by Tcf7)Essential role in T cell lineage specificationEvidence:TCF-1 is required for the generation of all known adult ILCsPART IIThe Transcriptional Regu

25、lation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 1: generation of CILCPs)Yang Q, Li F, Harly C, et al. TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol 2015;16:1044-50.TCF-1 up-regulation identify EILPs in bone marrowPART IIThe Transcr

26、iptional Regulation of Innate Lymphoid Cell DevelopmentTCF-1: T cell factor 1Essential role in T cell lineage specificationEvidence:TCF-1 is required for the generation of all known adult ILCsTCF-1 identifies a Early Innate lymphoid ProgenitorDeveloping Scheme (Stage 1: generation of CILCPs)Yang Q,

27、Li F, Harly C, et al. TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol 2015;16:1044-50.TCF-1 up-regulation identify EILPs in bone marrowPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentTCF-1: T cell factor 1Essential role in T ce

28、ll lineage specificationEvidence:TCF-1 is required for the generation of all known adult ILCsTCF-1 identifies a Early Innate lymphoid ProgenitorEILPs efficiently give rise to all ILC lineages in vivoDeveloping Scheme (Stage 1: generation of CILCPs)Seehus CR, Aliahmad P, de la Torre B, et al. The dev

29、elopment of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nat Immunol 2015;16:599-608.CLP-LPNKPILC2PPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentTOX:Thymocyte selection-associated high mobility group box proteinEssent

30、ial role in T cell subsets developmentEvidence:TOX is required for the development of ILC progenitors. TOX promotes CILCP generationDeveloping Scheme (Stage 1: generation of CILCPs)Seehus CR, Aliahmad P, de la Torre B, et al. The development of innate lymphoid cells requires TOX-dependent generation

31、 of a common innate lymphoid cell progenitor. Nat Immunol 2015;16:599-608.PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentTOX:Thymocyte selection-associated high mobility group box proteinEssential role in T cell subsets developmentEvidence:TOX is required for the developmen

32、t of ILC progenitors. TOX is required for the development of mature ILCs.TOX promotes CILCP generationDeveloping Scheme (Stage 1: generation of CILCPs)Seehus CR, Aliahmad P, de la Torre B, et al. The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid c

33、ell progenitor. Nat Immunol 2015;16:599-608.PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentTOX:Thymocyte selection-associated high mobility group box proteinEssential role in T cell subsets developmentEvidence:TOX is required for the development of ILC progenitors. TOX is r

34、equired for the development of mature ILCs.ILC gene program is blocked in Tox/ 47+ progenitorTOX promotes CILCP generationDeveloping Scheme (Stage 2: diversification of three main ILC groups)Serafini N, Vosshenrich CA, Di Santo JP. Transcriptional regulation of innate lymphoid cell fate. Nat Rev Imm

35、unol 2015;15:415-28.Transcriptional regulation of ILC diversificationEssential transcriptional factorsNK cells: ETS1, TOX, EOMESILC1s: IL-15, T-betILC2s: GATA3, ROR, TCF1, GFI1ILC3s: RORt, AHRPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 2: diversi

36、fication of three main ILC groups)Serafini N, Vosshenrich CA, Di Santo JP. Transcriptional regulation of innate lymphoid cell fate. Nat Rev Immunol 2015;15:415-28.Specification of Nature Killer cellsTranscriptional regulatory network:EOMESTOXETS1T-betRunx3PART IIThe Transcriptional Regulation of Inn

37、ate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 2: diversification of three main ILC groups)Simonetta F, Pradier A, Roosnek E. T-bet and Eomesodermin in NK Cell Development, Maturation, and Function. Front Immunol 2016;7:241.EOMES and T-bet in NK cell development and maturationEOMES & T-bet:T-

38、box transcription factorsCD8+ T cell developmentIFN- productionPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentzDeveloping Scheme (Stage 2: diversification of three main ILC groups)Differentiation of ILC1s: ETS1ETS1-deficient NK cells T-bet & Id2 Ramirez K, Chandler KJ, Spau

39、lding C, et al. Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1. Immunity 2012;36:921-32.Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.PART IIThe Transcriptiona

40、l Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 2: diversification of three main ILC groups)Aliahmad P, de la Torre B, Kaye J. Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat Immunol 2010;11:945-52

41、.TOX and Runx3 in NK cell development and maturationTOX:high expression in NKsintrinsic requirement of NK development Runx3:NK maturation(CD122, Ly49, IFN-)PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 2: diversification of three main ILC groups)Li

42、m AW, McKenzie AN. Deciphering the transcriptional switches of innate lymphoid cell programming: the right factors at the right time. Genes and immunity 2015;16:177-86.Specification of ILC1sPLZF+ CHILP ILC1 T-betILC3 ILC1 T-betPART IIThe Transcriptional Regulation of Innate Lymphoid Cell Development

43、Developing Scheme (Stage 2: diversification of three main ILC groups)Serafini N, Vosshenrich CA, Di Santo JP. Transcriptional regulation of innate lymphoid cell fate. Nat Rev Immunol 2015;15:415-28.Specification of ILC2sGATA3RORTCF1GFI1PART IIThe Transcriptional Regulation of Innate Lymphoid Cell De

44、velopmentDeveloping Scheme (Stage 2: diversification of three main ILC groups)Tindemans I, Serafini N, Di Santo JP, Hendriks RW. GATA-3 function in innate and adaptive immunity. Immunity 2014;41:191-206.Specification of ILC2s: GATA-3PART IIThe Transcriptional Regulation of Innate Lymphoid Cell Devel

45、opmentGATA-3: zinc finger transcriptorBroad involvement in innate &adaptive immunityDeveloping Scheme (Stage 2: diversification of three main ILC groups)Ishizuka IE, Constantinides MG, Gudjonson H, Bendelac A. The Innate Lymphoid Cell Precursor. Annu Rev Immunol 2016;34:299-316.PART IIThe Transcript

46、ional Regulation of Innate Lymphoid Cell DevelopmentGATA-3: zinc finger transcriptorBroad involvement in innate &adaptive immunityLogicality:GATA3 Type II cytokines ILCP ILC2s (Type II immunity)GATA3 required for:Type II cytokines productionRecruitment of immune cellsWorm expulsionSpecification of I

47、LC2s: GATA-3Developing Scheme (Stage 2: diversification of three main ILC groups)Wong SH, Walker JA, Jolin HE, et al. Transcription factor RORalpha is critical for nuocyte development. Nat Immunol 2012;13:229-36.Specification of ILC2s: RORPART IIThe Transcriptional Regulation of Innate Lymphoid Cell

48、 DevelopmentROR: nuclear hormone receptor TFBroad involvement in developmentResults:ROR deficiency(in vitro)ILC2(nuocytes) generation Developing Scheme (Stage 2: diversification of three main ILC groups)Wong SH, Walker JA, Jolin HE, et al. Transcription factor RORalpha is critical for nuocyte develo

49、pment. Nat Immunol 2012;13:229-36.PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentROR: nuclear hormone receptor TFBroad involvement in developmentResults:ROR deficiency(in vitro)ILC2(nuocytes) generation ROR deficiency(in vivo)ILC2(nuocytes) generation Specification of ILC2s

50、: RORDeveloping Scheme (Stage 2: diversification of three main ILC groups)Yang Q, Monticelli LA, Saenz SA, et al. T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 2013;38:694-704.Specification of ILC2s: TCF-1PART IIThe Transcriptional Regulation of Innate Lymphoid Ce

51、ll DevelopmentPrevious study:Notch signal block ILC2 generation Notch signal restore ILC2 generation restoreResults:TCF-1 ablationILC2 generation Developing Scheme (Stage 2: diversification of three main ILC groups)Walker JA, Oliphant CJ, Englezakis A, et al. Bcl11b is essential for group 2 innate l

52、ymphoid cell development. J Exp Med 2015;212:875-82.PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentSpecification of ILC2s: Bcl11bPrevious study:Notch signal block ILC2 generation Notch signal restore ILC2 generation restoreResults:TCF-1 ablationILC2 generation Bcl11b ablati

53、onILC2 generation Developing Scheme (Stage 2: diversification of three main ILC groups)Spooner CJ, Lesch J, Yan D, et al. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat Immunol 2013;14:1229-36.Specification of ILC2s: GFI1PART IIThe Transcriptional Regulation

54、of Innate Lymphoid Cell DevelopmentGFI1: zinc finger TFBroadly expressed in the hematopoietic system Results:CLP ILC2P ILC2: GFI1 Gfi1-/-: fewer ILC2Psloss of response to IL-33 inductiondefects in infection responseDeveloping Scheme (Stage 2: diversification of three main ILC groups)Spooner CJ, Lesc

55、h J, Yan D, et al. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat Immunol 2013;14:1229-36.PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentGFI1: zinc finger TFBroadly expressed in the hematopoietic system Results:CLP ILC2P ILC2: GFI1 G

56、fi1-/-: fewer ILC2Psloss of response to IL-33 inductiondefects in infection responseSpecification of ILC2s: GFI1Developing Scheme (Stage 2: diversification of three main ILC groups)Spooner CJ, Lesch J, Yan D, et al. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1.

57、Nat Immunol 2013;14:1229-36.PART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentGFI1: zinc finger TFBroadly expressed in the hematopoietic system Results:CLP ILC2P ILC2: GFI1 Gfi1-/-: fewer ILC2Psloss of response to IL-33 inductiondefects in infection responseSpecification of IL

58、C2s: GFI1Developing Scheme (Stage 2: diversification of three main ILC groups)Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A committed precursor to innate lymphoid cells. Nature 2014;508:397-401.Aliahmad P, de la Torre B, Kaye J. Shared dependence on the DNA-binding factor TOX for the dev

59、elopment of lymphoid tissue-inducer cell and NK cell lineages. Nat Immunol 2010;11:945-52.Tachibana M, Tenno M, Tezuka C, Sugiyama M, Yoshida H, Taniuchi I. Runx1/Cbfbeta2 complexes are required for lymphoid tissue inducer cell differentiation at two developmental stages. J Immunol 2011;186:1450-7.S

60、pecification of LTi cellPLZF- progenitor:specify LTiP from CHILPTOX: dependent in developmentRunx1:activate RoRt expression at anlagenPART IIThe Transcriptional Regulation of Innate Lymphoid Cell DevelopmentDeveloping Scheme (Stage 2: diversification of three main ILC groups)Scoville SD, Mundy-Bosse