1、Balance Between Th17/ Treg CellsInduced by Intestinal MicrobiotaContents從腸道菌群說起腸道菌群概述免疫系統對腸道菌群的調控Treg/Th17細胞的分化Th細胞概述Th17細胞的分化Treg細胞的分化Th17/Treg的可塑性腸道菌群對Treg/Th17平衡的調控腸道菌群調控免疫偽裝:修飾LPS腸道菌群調控免疫代謝產物刺激腸道菌群調控免疫粘附能力腸道菌群調控免疫特殊物質延伸與展望衛生假說從腸道菌群說起100TrillionMicrobial cells2-20MillionMicrobial genes3.0Poundspe

2、r personMicrobes in your body從腸道菌群說起Microbiota in your intestineBacteroidetes 擬桿菌Firmicutes 厚壁菌Proteobacteria 變形菌Chung, H.; Pamp, S. J.; Hill, J. A. et al, Gut immune maturation depends on colonization with a host-specific microbiota. Cell 2012, 149 (7), 1578-93.從腸道菌群說起What if there is no microbiota

3、?Marked reduction of IgA secretionLoss of the barrier against pathogenic organismsDefect in Gut-associated lymphoid tissueDefect in the development of intestinal epithelial cellsReduction of antimicrobial peptide production by paneth cellsDefect in T cells differentiation Cause of inflammation, IBD,

4、 cancer, etc. 免疫系統對腸道菌群的調控Segregation Outer/inner mucus layerSecretion IgA, IgM interleukin -defensins, RegIII Adhesion DC MacrophageHooper, L. V.; Littman, D. R. et al; Macpherson, A. J., Interactions between the microbiota and the immune system. Science 2012, 336 (6086), 1268-73.從腸道菌群說起免疫系統對腸道菌群的調

5、控TLRs signalingPromote mucin(黏蛋白) and antibacterial protein(RegIII, IgA, and IgM)Promote interaction between DC and microbiotaVaishnava, Shipra et al. “The Antibacterial Lectin RegIII Promotes the Spatial Segregation of Microbiota and Host in the Intestine.”Science 334.6053 (2011)從腸道菌群說起Th17 & Treg

6、細胞Treg/Th17細胞的分化Chen Z, OShea JJ. Th17 cells: a new fate for differentiating helper T cells. Immunol Res 2008; 41: 87-102Th17 細胞的分化Treg/Th17細胞的分化Initiation: IL-6 and TGF-Costimulation by IL-6&TGF-: Th17, TregOnly by TGF-: Treg Maintenance and expansion: IL-23Low IL-23R expression in Nave CD4 + T cel

7、lsAutocrine factor: IL-21IL-6 and TGF- stimulate IL-21 expressionReplace IL-6 to induce IL-17, 21 and IL-23R expressionTreg 細胞的分化Treg/Th17細胞的分化Treg cellsnature Treg cells(nTreg)induced Treg cells(iTreg)nTreg: CD25+CD4+ FOXP3 + cells require intermediate TCR signaling, IL-2 iTreg: CD25+CD4+ FOXP3 + c

8、ells require low TCR and exogenous antigen signaling require TGF- and RATF FOXP3 is the crucial factor of Treg differentiation Treg 細胞的分化Treg/Th17細胞的分化Josefowicz, S. Z.; Lu, L. F.; Rudensky, A. Y. et al, Regulatory T cells: mechanisms of differentiation and function. Annual review of immunology 2012

9、, 30, 531-64.Th17/Treg 可塑性Treg/Th17細胞的分化Ueno, A.; Ghosh, A. et al, Th17 plasticity and its changes associated with inflammatory bowel disease. World journal of gastroenterology 2015, 21 (43), 12283-95.腸道菌群調控Treg/Th17平衡Geuking, M. B.; Cahenzli, J.; Lawson, M. A. et al, Intestinal bacterial colonizati

10、on induces mutualistic regulatory T cell responses. Immunity 2011, 34 (5), 794-806.Intestinal colonization results in proliferation and activation of Treg cells偽裝修飾LPSCD14 binds to LPS with help of LBPLPS transports to TLR4-MD2 complexTLR4 activatedInflammatory Endocytosis: TLR4 as cargoActivate MyD

11、88 pathway and TRIF pathwayInflammatory cytokines and IFN secretionT cell immune response腸道菌群對Treg/Th17平衡的調控偽裝修飾LPS腸道菌群對Treg/Th17平衡的調控Ec-LPS: LPS from E. coliB. thetaiotaomicron LPS(Bt-LPS): monophosphorylated Lipid ALpxF phosphatase: responsible for producing monophosphorylated Lipid A CD14 recogni

12、zes LPS and help TLR4/MD-2 DimerizationTan, Y.; Zanoni, I.; Cullen, ThomasW. et al, Mechanisms of Toll-like Receptor 4 Endocytosis Reveal a Common Immune-Evasion Strategy Used by Pathogenic and Commensal Bacteria. Immunity, 2015, 43 (5), 909-922.代謝產物刺激腸道菌群對Treg/Th17平衡的調控Clostridia 梭狀芽孢桿菌A dominant c

13、lass of commensal microbe, Gram+ can induce colonic regulatory T (Treg) cellsProduce short-chain fatty acid (SCFA) during starch fermentationSCFA include butyrate, propionate, acetate, etc.butyrate induced the differentiation of Treg cells in vitro and in vivo代謝產物刺激腸道菌群對Treg/Th17平衡的調控Furusawa, Y.; O

14、bata, Y.; Fukuda, S. et al, Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504 (7480), 446-50.Arpaia, N.; Campbell, C.; Fan, X. et al, Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013,

15、504 (7480), 451-5.代謝產物刺激腸道菌群對Treg/Th17平衡的調控De Zoeten, Edwin F. et al. “Inhibition of HDAC9 Increases T Regulatory Cell Function and Prevents Colitis in Mice.”Gastroenterology138.2 (2010): 583594.MechanismButyrate can regulate gene expression epigenetically by inhibiting histone deacetylases (HDACs)H

16、DAC suppress Treg cell expansionFoxp3 were acetylated after butyrate exposureButyrate upregulated histone H3 acetylation at both the promoter and the enhancer代謝產物刺激腸道菌群對Treg/Th17平衡的調控Long-chain fatty acids(LCFAs) enhanced differentiation and proliferation of Th1 and Th17 cells via p38-MAPK pathwaySh

17、ort-chain FAs (SCFAs) expanded gut Treg cellsImpact CNS by regulating response to experimental autoimmune encephalomyelitis (EAE)Haghikia, A.; Jorg, S.; Duscha, A. et al, Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. Immunity 2015, 43 (4), 817-29.粘附

18、能力SFB腸道菌群對Treg/Th17平衡的調控Segmented filamentous bacteria 分節絲狀菌Spore-forming, gram-positive, segmented and filamentousTight adhesion to SI epithelial cells (Ecs)Has host specificityAtarashi, K.; Tanoue, T.; Ando, M., Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell 2015,

19、 163 (2), 367-80.粘附能力SFB腸道菌群對Treg/Th17平衡的調控MechanismAdhering SFB induce actin reorganization in SI ECsUpregulation of serum amyloid A(SAA) expressionSAA1 enhances Th17 cell differentiation with the help of IL-1, IL-6, TGF-SAA1 can also upregulate IL-1 expressionAtarashi, K.; Tanoue, T.; Ando, M., Th

20、17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell 2015, 163 (2), 367-80.Pedicord, V. A.; Mucida, D., A Sledgehammer Breaks Glass but Forges Steel: Bacteria Adhesion Shapes Gut Immunity. Cell 2015, 163 (2), 273-4.粘附能力SFB腸道菌群對Treg/Th17平衡的調控More researches show some pathoge

21、nic microbes and some strains derived from human have EC-adhering abilityThe difference between pathogenic microbes and microbiota is whether they can penetrate the EC layer or not.特殊物質PSA腸道菌群對Treg/Th17平衡的調控Bacteroides fragilis 脆弱擬桿菌Gram-negative anaerobes in the human microbiotaProduce Polysacchari

22、de A (PSA) as a symbiosis factorPSA activate the TLR pathway of Tregs Require TLR2 signalingHowever, Toll-like Receptor 2 Signaling in CD4+ T Lymphocytes Promotes T Helper 17 Responses腸道菌群對Treg/Th17平衡的調控特殊物質PSARound, J. L.; Lee, S. M.; Li, J., The Toll-like receptor 2 pathway establishes colonizatio

23、n by a commensal of the human microbiota. Science 2011, 332 (6032), 974-7.腸道菌群對Treg/Th17平衡的調控特殊物質PSAAfter exposed to PSA in vitro, Th17 express pro-inflammatory function while Treg anti-inflammatoryThe immunoprotective ability of PSA depends on DCs exposureDCs include Plasmacytoid DCs(PDC) and conve

24、ntional DCs(CDC)PDC and CDC have different response to PSAPDC induce IFN and IL-10 mediated by PSA, which promotes Treg functionPDC induce Molecular mediators including MHCII, ICOSL, CD86, and promote Treg generationPSA can also activate the TLR2 signaling of Tregs directly腸道菌群對Treg/Th17平衡的調控特殊物質PSADasgupta, S.; Erturk-Hasdemir, D.; Ochoa-Reparaz, J., Plasmacytoid dendritic cells mediate anti-inflam