Development and maintenance of intestinal regulatory T cells

Nature Reviews Immunology

Volumn 16, Issue 5, 2016, Pages 295-309

  Tanoue, Takeshi ^a   Atarashi, Koji ^a,b   Honda, Kenya ^a,b,c  

^a Institute of Physical and Chemical Research   (Japan)

^b KEIO UNIVERSITY   (Japan)

^c JAPAN AGENCY FOR MEDICAL RESEARCH AND DEVELOPMENT   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 10; RETINOID RELATED ORPHAN RECEPTOR GAMMA; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR GATA 3;

ADOPTIVE TRANSFER; ANIMAL CELL; CELL DIFFERENTIATION; CELL MIGRATION; COMMENSAL; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNOREGULATION; INTESTINE CELL; INTESTINE FLORA; MOUSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; ANIMAL; CLONAL EVOLUTION; CYTOLOGY; GENETICS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; METABOLISM; MUCOSAL IMMUNITY; PEYER PATCH; PHYSIOLOGY; T LYMPHOCYTE SUBPOPULATION; TUMOR MICROENVIRONMENT;

ANIMALS; CELL DIFFERENTIATION; CELLULAR MICROENVIRONMENT; CLONAL EVOLUTION; GASTROINTESTINAL MICROBIOME; HUMANS; IMMUNE TOLERANCE; IMMUNITY, MUCOSAL; PEYER'S PATCHES; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 84964403670     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2016.36     Document Type: Review

References (139)

1. Xavier, R. J., & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427-434 (2007).
2. Maloy, K. J., & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298-306 (2011).
3. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M. Immunologic self-Tolerance maintained by activated T cells expressing IL 2 receptor α-chains (CD25). Breakdown of a single mechanism of self-Tolerance causes various autoimmune diseases. J. Immunol. 155, 1151-1164 (1995).
4. Mottet, C., Uhlig, H. H., & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939-3943 (2003).
5. Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330-336 (2003).
6. Hori, S., Nomura, T., & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061 (2003).
7. Khattri, R., Cox, T., Yasayko, S. A., & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337-342 (2003).
8. Brunkow, M. E. et al. Disruption of a new forkhead/ winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68-73 (2001).
9. Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57-63 (2007).
10. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329-341 (2005).
11. Mayer, C. T. et al. Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity. Eur. J. Immunol. 44, 2990-3002 (2014).
12. Chatila, T. A. et al. JM2, encoding a fork head-related protein, is mutated in X linked autoimmunity-Allergic disregulation syndrome. J. Clin. Invest. 106, R75-R81 (2000).
13. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20-21 (2001).
14. Wildin, R. S. et al. X linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18-20 (2001).
15. Langer, L. F., Clay, T. M., & Morse, M. A. Update on anti-CTLA 4 antibodies in clinical trials. Expert Opin. Biol. Ther. 7, 1245-1256 (2007).
16. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin 10 receptor. N. Engl. J. Med. 361, 2033-2045 (2009).
17. Groux, H. et al. A CD4+ T cell subset inhibits antigen-specific T cell responses and prevents colitis. Nature 389, 737-742 (1997).
18. Okamura, T. et al. TGF β3 expressing CD4+CD25-LAG3+ regulatory T cells control humoral immune responses. Nat. Commun. 6, 6329 (2015).
19. Round, J. L., & Mazmanian, S. K. Inducible Foxp3+ regulatory T cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204-12209 (2010).
20. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337-341 (2011).
21. Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794-806 (2011).
22. Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723-42 (2012).
23. Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145-13150 (2014).
24. Collison, L. W. et al. The inhibitory cytokine IL 35 contributes to regulatory T cell function. Nature 450, 566-569 (2007).
25. Li, M. O., Wan, Y. Y., & Flavell, R. A. T cell-produced transforming growth factor β1 controls T cell tolerance and regulates Th1-And Th17 cell differentiation. Immunity 26, 579-591 (2007).
26. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin 10 limits inflammation at environmental interfaces. Immunity 28, 546-558 (2008).
27. Wing, K. et al. CTLA 4 control over Foxp3+ regulatory T cell function. Science 322, 271-275 (2008).
28. Zheng, Y. et al. Regulatory T cell suppressor program co opts transcription factor IRF4 to control TH2 responses. Nature 458, 351-356 (2009).
29. Herman, A. E., Freeman, G. J., Mathis, D., & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479-1489 (2004).
30. Kawamoto, S. et al. Foxp3+ T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152-165 (2014).
31. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R., & Elson, C. O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256-19261 (2009).
32. Maloy, K. J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111-119 (2003).
33. Kim, S. V. et al. GPR15 mediated homing controls immune homeostasis in the large intestine mucosa. Science 340, 1456-1459 (2013).
34. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232-236 (2013).
35. Kim, K. S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858-663 (2016).
36. Curotto de Lafaille, M. A., & Lafaille, J. J. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity 30, 626-635 (2009).
37. Curotto de Lafaille, M. A. et al. Adaptive Foxp3+ regulatory T cell-dependent and-independent control of allergic inflammation. Immunity 29, 114-126 (2008).
38. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757-1764 (2007).
39. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775-1785 (2007).
40. Haribhai, D. et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35, 109-122 (2011).
41. Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433-3441 (2010).
42. Yadav, M. et al. Neuropilin 1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713-1722 (2012).
43. Gottschalk, R. A., Corse, E., & Allison, J. P. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J. Immunol. 188, 976-980 (2012).
44. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T cell fate. Nature 463, 808-812 (2010).
45. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194-202 (2008).
46. Xu, L Et Al. Positive and Negative Transcriptional Regulation of the Foxp3 Gene Is Mediated by Access and Binding of the Smad3 Protein to Enhancer I. Immunity 33, 313-325 (2010).
47. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395-399 (2012).
48. Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250-254 (2011).
49. Cebula, A. et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497, 258-262 (2013).
50. Korn, L. L. et al. Regulatory T cells occupy an isolated niche in the intestine that is antigen independent. Cell Rep. 9, 1567-1573 (2014).
51. Nishio, J. et al. Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis. Proc. Natl Acad. Sci. USA 112, 12770-12775 (2015).
52. Feuerer, M. et al. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc. Natl Acad. Sci. USA 107, 5919-5924 (2010).
53. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899-911 (2009).
54. Murai, M., Krause, P., Cheroutre, H., & Kronenberg, M. Regulatory T cell stability and plasticity in mucosal and systemic immune systems. Mucosal Immunol. 3, 443-449 (2010).
55. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer?s patches. Science 323, 1488-1492 (2009).
56. Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785-799 (2012).
57. Morikawa, H. et al. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl Acad. Sci. USA 111, 5289-5294 (2014).
58. Ono, M. et al. Foxp3 controls regulatory T cell function by interacting with AML1/Runx1. Nature 446, 685-689 (2007).
59. Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749-763 (2014).
60. Li, X., Liang, Y., LeBlanc, M., Benner, C., & Zheng, Y. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158, 734-748 (2014).
61. Yang, B. H. et al. Foxp3 T cells expressing ROR?t represent a stable regulatory T cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 9, 444-457 (2016).
62. Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E., & Waldmann, H. The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461-467 (2013).
63. Miyao, T. et al. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262-275 (2012).
64. Koch, M. A. et al. The transcription factor T bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595-602 (2009).
65. Wohlfert, E. A. et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503-4515 (2011).
66. Rudra, D. et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat. Immunol. 13, 1010-1019 (2012).
67. Yu, F., Sharma, S., Edwards, J., Feigenbaum, L., & Zhu, J. Dynamic expression of transcription factors T bet and GATA 3 by regulatory T cells maintains immunotolerance. Nat. Immunol. 16, 197-206 (2015).
68. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl 6 suppress germinal center reactions. Nat. Med. 17, 983-988 (2011).
69. Lochner, M. et al. Restricted microbiota and absence of cognate TCR antigen leads to an unbalanced generation of Th17 cells. J. Immunol. 186, 1531-1537 (2011).
70. Ohnmacht, C. et al. The microbiota regulates type 2 immunity through ROR?t+ T cells. Science 349, 989-993 (2015).
71. Sefik, E. et al. Individual intestinal symbionts induce a distinct population of ROR?+ regulatory T cells. Science 349, 993-997 (2015).
72. Schiering, C. et al. The alarmin IL 33 promotes regulatory T cell function in the intestine. Nature 513, 564-568 (2014).
73. Griseri, T., Asquith, M., Thompson, C., & Powrie, F. OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699-709 (2010).
74. Liston, A., & Gray, D. H. Homeostatic control of regulatory T cell diversity. Nat. Rev. Immunol. 14, 154-165 (2014).
75. Levine, A. G., Arvey, A., Jin, W., & Rudensky, A. Y. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15, 1070-1078 (2014).
76. Cretney, E. et al. The transcription factors Blimp 1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 12, 304-311 (2011).
77. Maynard, C. L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3-precursor cells in the absence of interleukin 10. Nat. Immunol. 8, 931-941 (2007).
78. Kamanaka, M. et al. Expression of interleukin 10 in intestinal lymphocytes detected by an interleukin 10 reporter knockin tiger mouse. Immunity 25, 941-952 (2006).
79. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39-49 (1999).
80. Huber, S. et al. Th17 cells express interleukin 10 receptor and are controlled by Foxp3-And Foxp3+ regulatory CD4+ T cells in an interleukin 10 dependent manner. Immunity 34, 554-565 (2011).
81. Park, S. G. et al. T regulatory cells maintain intestinal homeostasis by suppressing T cells. Immunity 33, 791-803 (2010).
82. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3 dependent manner. Science 326, 986-991 (2009).
83. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T cell stimulation. Nature 445, 931-935 (2007).
84. Chaudhry, A. et al. Interleukin 10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566-578 (2011).
85. Itoh, K., & Mitsuoka, T. Characterization of clostridia isolated from faeces of limited flora mice and their effect on caecal size when associated with germ-free mice. Lab Anim. 19, 111-118 (1985).
86. Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731-16736 (2008).
87. Sarrabayrouse, G. et al. CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLoS Biol. 12, e1001833 (2014).
88. Narushima, S. et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5, 333-339 (2014).
89. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569-573 (2013).
90. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446-450 (2013).
91. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451-455 (2013).
92. Di Giacinto, C., Marinaro, M., Sanchez, M., Strober, W., & Boirivant, M. Probiotics ameliorate recurrent Th1 mediated murine colitis by inducing IL 10 and IL 10 dependent TGFβ-bearing regulatory cells. J. Immunol. 174, 3237-3246 (2005).
93. Karimi, K., Inman, M. D., Bienenstock, J., & Forsythe, P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 179, 186-193 (2009).
94. Tang, C. et al. Inhibition of dectin 1 signaling ameliorates colitis by inducing Lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 18, 183-197 (2015).
95. Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509-520 (2012).
96. Faith, J. J., Ahern, P. P., Ridaura, V. K., Cheng, J., & Gordon, J. I. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl Med. 6, 220ra11 (2014).
97. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256-260 (2007).
98. Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E., & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724-3733 (2007).
99. DePaolo, R. W. et al. Co adjuvant effects of retinoic acid and IL 15 induce inflammatory immunity to dietary antigens. Nature 471, 220-224 (2011).
100. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235-238 (2006).
101. Kang, S. W. et al. 1,25 Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J. Immunol. 188, 5276-5282 (2012).
102. Yamaguchi, T. et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27, 145-159 (2007).
103. Kinoshita, M. et al. Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. J. Immunol. 189, 2869-2878 (2012).
104. Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190-3198 (2010).
105. Wang, J. et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281, 22021-22028 (2006).
106. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012).
107. Zandi-Nejad, K. et al. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J. 27, 4366-4374 (2013).
108. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128-139 (2014).
109. Farache, J. et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38, 581-595 (2013).
110. McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345-349 (2012).
111. Hickey, C. A. et al. Colitogenic Bacteroides thetaiotaomicron antigens access host immune cells in a sulfatase-dependent manner via outer membrane vesicles. Cell Host Microbe 17, 672-680 (2015).
112. Travis, M. A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361-365 (2007).
113. Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780-791 (2011).
114. Persson, E. K. et al. IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38, 958-969 (2013).
115. Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL 17 cytokine responses. Immunity 38, 970-983 (2013).
116. Welty, N. E. et al. Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. J. Exp. Med. 210, 2011-2024 (2013).
117. Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823-836 (2010).
118. Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115-3130 (2009).
119. Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849-853 (2010).
120. Mosconi, I. et al. Intestinal bacteria induce TSLP to promote mutualistic T cell responses. Mucosal Immunol. 6, 1157-1167 (2013).
121. Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat. Immunol. 6, 507-514 (2005).
122. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).
123. Hadis, U. et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34, 237-246 (2011).
124. Honda, K., & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759-795 (2012).
125. van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407-415 (2013).
126. Kump, P. K. et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm. Bowel Dis. 19, 2155-2165 (2013).
127. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780-13785 (2007).
128. Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl Med. 7, 307ra152 (2015).
129. Miyake, S. et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS ONE 10, e0137429 (2015).
130. Kashiwagi, I. et al. Smad2 and Smad3 inversely regulate TGF-β autoinduction in Clostridium butyricum-Activated dendritic cells. Immunity 43, 65-79 (2015).
131. Hayashi, A. et al. A single strain of Clostridium butyricum induces intestinal IL 10 producing macrophages to suppress acute experimental colitis in mice. Cell Host Microbe 13, 711-722 (2013).
132. Calcinaro, F. et al. Oral probiotic administration induces interleukin 10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48, 1565-1575 (2005).
133. Li, Y. N. et al. Effect of oral feeding with Clostridium leptum on regulatory T cell responses and allergic airway inflammation in mice. Ann. Allergy Asthma Immunol. 109, 201-207 (2012).
134. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974-977 (2011).
135. Dasgupta, S., Erturk-Hasdemir, D., Ochoa-Reparaz, J., Reinecker, H. C., & Kasper, D. L. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 15, 413-423 (2014).
136. Jang, S. O. et al. Asthma prevention by Lactobacillus Rhamnosus in a mouse model is associated with CD4+CD25+Foxp3+ T Cells. Allergy Asthma Immunol. Res. 4, 150-156 (2012).
137. Lavasani, S. et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL 10 producing regulatory T cells. PLoS ONE 5, e9009 (2010).
138. Wang, S. et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43, 289-303 (2015).
139. Kunisawa, J., Hashimoto, E., Ishikawa, I., & Kiyono, H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS ONE 7, e32094 (2012).