Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 331 (6015): 337-341

Copyright © 2011 by the American Association for the Advancement of Science

Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species

Koji Atarashi,1,* Takeshi Tanoue,1,* Tatsuichiro Shima,2 Akemi Imaoka,2 Tomomi Kuwahara,3 Yoshika Momose,4 Genhong Cheng,5 Sho Yamasaki,6 Takashi Saito,6 Yusuke Ohba,7 Tadatsugu Taniguchi,1 Kiyoshi Takeda,8 Shohei Hori,9 Ivaylo I. Ivanov,10 Yoshinori Umesaki,2 Kikuji Itoh,4 Kenya Honda1,11,{dagger}

Abstract: CD4+ T regulatory cells (Tregs), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis. Here, we show that in mice, Tregs were most abundant in the colonic mucosa. The spore-forming component of indigenous intestinal microbiota, particularly clusters IV and XIVa of the genus Clostridium, promoted Treg cell accumulation. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in transforming growth factor–β and affected Foxp3+ Treg number and function in the colon. Oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic immunoglobulin E responses in adult mice, suggesting a new therapeutic approach to autoimmunity and allergy.

1 Department of Immunology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
2 Yakult Central Institute for Microbiological Research, Tokyo 186-8650, Japan.
3 Department of Molecular Bacteriology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
4 Department of Veterinary Public Health, University of Tokyo, Tokyo 113-8657, Japan.
5 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
6 Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
7 Laboratory of Pathophysiology and Signal Transduction, Hokkaido University, Graduate School of Medicine, Sapporo 060-8638, Japan.
8 Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
9 Research Unit for Immune Homeostasis, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
10 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
11 Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kenya{at}m.u-tokyo.ac.jp


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Metatranscriptomics of the Human Oral Microbiome during Health and Disease.
P. Jorth, K. H. Turner, P. Gumus, N. Nizam, N. Buduneli, and M. Whiteley (2014)
mBio 5, e01012-14
   Abstract »    Full Text »    PDF »
Altered Fecal Microbiota Composition Associated with Food Allergy in Infants.
Z. Ling, Z. Li, X. Liu, Y. Cheng, Y. Luo, X. Tong, L. Yuan, Y. Wang, J. Sun, L. Li, et al. (2014)
Appl. Envir. Microbiol. 80, 2546-2554
   Abstract »    Full Text »    PDF »
Antibiotics Help Control Rotavirus Infections and Enhance Antirotaviral Immunity: Are You Serious?.
L. A. Bartelt and R. L. Guerrant (2014)
The Journal of Infectious Disease
   Full Text »    PDF »
Consumption of Acidic Water Alters the Gut Microbiome and Decreases the Risk of Diabetes in NOD Mice.
K. J. Wolf, J. G. Daft, S. M. Tanner, R. Hartmann, E. Khafipour, and R. G. Lorenz (2014)
Journal of Histochemistry & Cytochemistry 62, 237-250
   Abstract »    Full Text »    PDF »
Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis.
A. Mortha, A. Chudnovskiy, D. Hashimoto, M. Bogunovic, S. P. Spencer, Y. Belkaid, and M. Merad (2014)
Science 343, 1249288
   Abstract »    Full Text »    PDF »
Salmonella enterica Serovar Typhimurium Infection-Induced CD11b+ Gr1+ Cells Ameliorate Allergic Airway Inflammation.
V. Ganesh, A. M. Baru, C. Hesse, C. Friedrich, S. Glage, M. Gohmert, C. Janke, and T. Sparwasser (2014)
Infect. Immun. 82, 1052-1063
   Abstract »    Full Text »    PDF »
Transcription factors controlling development and function of innate lymphoid cells.
Y. Tanriver and A. Diefenbach (2014)
Int. Immunol. 26, 119-128
   Abstract »    Full Text »    PDF »
The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition.
P. V. Chang, L. Hao, S. Offermanns, and R. Medzhitov (2014)
PNAS 111, 2247-2252
   Abstract »    Full Text »    PDF »
Microbial metabolites control gut inflammatory responses.
N. Arpaia and A. Y. Rudensky (2014)
PNAS 111, 2058-2059
   Full Text »    PDF »
Identifying Gut Microbe-Host Phenotype Relationships Using Combinatorial Communities in Gnotobiotic Mice.
J. J. Faith, P. P. Ahern, V. K. Ridaura, J. Cheng, and J. I. Gordon (2014)
Science Translational Medicine 6, 220ra11
   Abstract »    Full Text »    PDF »
House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection.
K. E. Fujimura, T. Demoor, M. Rauch, A. A. Faruqi, S. Jang, C. C. Johnson, H. A. Boushey, E. Zoratti, D. Ownby, N. W. Lukacs, et al. (2014)
PNAS 111, 805-810
   Abstract »    Full Text »    PDF »
Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice.
C. B. Larmonier, D. Laubitz, F. M. Hill, K. W. Shehab, L. Lipinski, M. T. Midura-Kiela, R.-M. T. McFadden, R. Ramalingam, K. A. Hassan, M. Golebiewski, et al. (2013)
Am J Physiol Gastrointest Liver Physiol 305, G667-G677
   Abstract »    Full Text »    PDF »
Regulation of the immune system by biodiversity from the natural environment: An ecosystem service essential to health.
G. A. Rook (2013)
PNAS 110, 18360-18367
   Abstract »    Full Text »    PDF »
Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation.
M. Z. Cader and A. Kaser (2013)
Gut 62, 1653-1664
   Abstract »    Full Text »    PDF »
Location, location, location: tissue-specific regulation of immune responses.
W. Hu and C. Pasare (2013)
J. Leukoc. Biol. 94, 409-421
   Abstract »    Full Text »    PDF »
The gut microbiota and host innate immunity: Regulators of host metabolism and metabolic diseases in poultry?.
M. H. Kogut (2013)
J Appl Poult Res 22, 637-646
   Abstract »    Full Text »    PDF »
Divergent Immunomodulating Effects of Probiotics on T Cell Responses to Oral Attenuated Human Rotavirus Vaccine and Virulent Human Rotavirus Infection in a Neonatal Gnotobiotic Piglet Disease Model.
K. S. Chattha, A. N. Vlasova, S. Kandasamy, G. Rajashekara, and L. J. Saif (2013)
J. Immunol. 191, 2446-2456
   Abstract »    Full Text »    PDF »
Feed Your Tregs More Fiber.
J. Bollrath and F. Powrie (2013)
Science 341, 463-464
   Abstract »    Full Text »    PDF »
The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis.
P. M. Smith, M. R. Howitt, N. Panikov, M. Michaud, C. A. Gallini, M. Bohlooly-Y, J. N. Glickman, and W. S. Garrett (2013)
Science 341, 569-573
   Abstract »    Full Text »    PDF »
Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism.
I. Vujkovic-Cvijin, R. M. Dunham, S. Iwai, M. C. Maher, R. G. Albright, M. J. Broadhurst, R. D. Hernandez, M. M. Lederman, Y. Huang, M. Somsouk, et al. (2013)
Science Translational Medicine 5, 193ra91
   Abstract »    Full Text »    PDF »
ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice.
T. Ikuta, Y. Kobayashi, M. Kitazawa, K. Shiizaki, N. Itano, T. Noda, S. Pettersson, L. Poellinger, Y. Fujii-Kuriyama, S. Taniguchi, et al. (2013)
Carcinogenesis 34, 1620-1627
   Abstract »    Full Text »    PDF »
Regulatory T Cells and Immune Tolerance in the Intestine.
O. J. Harrison and F. M. Powrie (2013)
Cold Spring Harb Perspect Biol 5, a018341
   Abstract »    Full Text »    PDF »
GPR15-Mediated Homing Controls Immune Homeostasis in the Large Intestine Mucosa.
S. V. Kim, W. V. Xiang, C. Kwak, Y. Yang, X. W. Lin, M. Ota, U. Sarpel, D. B. Rifkin, R. Xu, and D. R. Littman (2013)
Science 340, 1456-1459
   Abstract »    Full Text »    PDF »
Total Parenteral Nutrition-Associated Lamina Propria Inflammation in Mice Is Mediated by a MyD88-Dependent Mechanism.
E. A. Miyasaka, Y. Feng, V. Poroyko, N. R. Falkowski, J. Erb-Downward, M. G. Gillilland III, K. L. Mason, G. B. Huffnagle, and D. H. Teitelbaum (2013)
J. Immunol. 190, 6607-6615
   Abstract »    Full Text »    PDF »
Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells.
T. Kawabe, S.-l. Sun, T. Fujita, S. Yamaki, A. Asao, T. Takahashi, T. So, and N. Ishii (2013)
J. Immunol. 190, 5788-5798
   Abstract »    Full Text »    PDF »
Local "On-Demand" Generation and Function of Antigen-Specific Foxp3+ Regulatory T Cells.
S. W. McPherson, N. D. Heuss, and D. S. Gregerson (2013)
J. Immunol. 190, 4971-4981
   Abstract »    Full Text »    PDF »
The Degree of Helicobacter pylori-Triggered Inflammation Is Manipulated by Preinfection Host Microbiota.
A. S. Rolig, C. Cech, E. Ahler, J. E. Carter, and K. M. Ottemann (2013)
Infect. Immun. 81, 1382-1389
   Abstract »    Full Text »    PDF »
An update on the use and investigation of probiotics in health and disease.
M. E. Sanders, F. Guarner, R. Guerrant, P. R. Holt, E. M. Quigley, R. B. Sartor, P. M. Sherman, and E. A. Mayer (2013)
Gut 62, 787-796
   Abstract »    Full Text »    PDF »
Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway.
J. M. Coquet, J. C. Ribot, N. Babala, S. Middendorp, G. van der Horst, Y. Xiao, J. F. Neves, D. Fonseca-Pereira, H. Jacobs, D. J. Pennington, et al. (2013)
J. Exp. Med. 210, 715-728
   Abstract »    Full Text »    PDF »
Exploring host-microbiota interactions in animal models and humans.
A. D. Kostic, M. R. Howitt, and W. S. Garrett (2013)
Genes & Dev. 27, 701-718
   Abstract »    Full Text »    PDF »
Welcome to the Microgenderome.
M. B. Flak, J. F. Neves, and R. S. Blumberg (2013)
Science 339, 1044-1045
   Abstract »    Full Text »    PDF »
Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity.
J. G. M. Markle, D. N. Frank, S. Mortin-Toth, C. E. Robertson, L. M. Feazel, U. Rolle-Kampczyk, M. von Bergen, K. D. McCoy, A. J. Macpherson, and J. S. Danska (2013)
Science 339, 1084-1088
   Abstract »    Full Text »    PDF »
Microbiota and Autoimmunity.
A. V. Chervonsky (2013)
Cold Spring Harb Perspect Biol 5, a007294
   Abstract »    Full Text »    PDF »
Probiotics: Properties, Examples, and Specific Applications.
J. Behnsen, E. Deriu, M. Sassone-Corsi, and M. Raffatellu (2013)
Cold Spring Harb Perspect Med 3, a010074
   Abstract »    Full Text »    PDF »
Role of the Gut Microbiota in the Development and Function of Lymphoid Cells.
N. Kamada and G. Nunez (2013)
J. Immunol. 190, 1389-1395
   Abstract »    Full Text »    PDF »
Primocolonization is associated with colonic epithelial maturation during conventionalization.
J. Tomas, L. Wrzosek, N. Bouznad, S. Bouet, C. Mayeur, M.-L. Noordine, E. Honvo-Houeto, P. Langella, M. Thomas, and C. Cherbuy (2013)
FASEB J 27, 645-655
   Abstract »    Full Text »    PDF »
Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.
J. U. Scher, A. Sczesnak, R. S. Longman, N. Segata, C. Ubeda, C. Bielski, T. Rostron, V. Cerundolo, E. G. Pamer, S. B. Abramson, et al. (2013)
eLife Sci 2, e01202
   Abstract »    Full Text »    PDF »
Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios.
J.-H. Weitkamp, T. Koyama, M. T. Rock, H. Correa, J. A. Goettel, P. Matta, K. Oswald-Richter, M. J. Rosen, B. G. Engelhardt, D. J. Moore, et al. (2013)
Gut 62, 73-82
   Abstract »    Full Text »    PDF »
Microbial 'Old Friends', immunoregulation and stress resilience.
G. A. W. Rook, C. A. Lowry, and C. L. Raison (2013)
EMPH 2013, 46-64
   Abstract »    Full Text »    PDF »
Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.
H. Negishi, S. Miki, H. Sarashina, N. Taguchi-Atarashi, A. Nakajima, K. Matsuki, N. Endo, H. Yanai, J. Nishio, K. Honda, et al. (2012)
PNAS 109, 21016-21021
   Abstract »    Full Text »    PDF »
Regulation of intestinal homeostasis by innate and adaptive immunity.
H. Kayama and K. Takeda (2012)
Int. Immunol. 24, 673-680
   Abstract »    Full Text »    PDF »
Th17 Cells Upregulate Polymeric Ig Receptor and Intestinal IgA and Contribute to Intestinal Homeostasis.
A. T. Cao, S. Yao, B. Gong, C. O. Elson, and Y. Cong (2012)
J. Immunol. 189, 4666-4673
   Abstract »    Full Text »    PDF »
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells.
J. M. Weiss, A. M. Bilate, M. Gobert, Y. Ding, M. A. Curotto de Lafaille, C. N. Parkhurst, H. Xiong, J. Dolpady, A. B. Frey, M. G. Ruocco, et al. (2012)
J. Exp. Med. 209, 1723-1742
   Abstract »    Full Text »    PDF »
Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T Cell Responses.
T. W. Hand, L. M. Dos Santos, N. Bouladoux, M. J. Molloy, A. J. Pagan, M. Pepper, C. L. Maynard, C. O. Elson III, and Y. Belkaid (2012)
Science 337, 1553-1556
   Abstract »    Full Text »    PDF »
Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation.
J. S. Bajaj, P. B. Hylemon, J. M. Ridlon, D. M. Heuman, K. Daita, M. B. White, P. Monteith, N. A. Noble, M. Sikaroodi, and P. M. Gillevet (2012)
Am J Physiol Gastrointest Liver Physiol 303, G675-G685
   Abstract »    Full Text »    PDF »
Editorial: Peer across the barrier--new live transmissions from the intestinal mucosa.
J. R. Murdoch and T. Junt (2012)
J. Leukoc. Biol. 92, 407-409
   Full Text »    PDF »
Innate immune signalling at the intestinal epithelium in homeostasis and disease.
J. Pott and M. Hornef (2012)
EMBO Rep. 13, 684-698
   Abstract »    Full Text »    PDF »
Quantitative assessment of the impact of the gut microbiota on lysine {varepsilon}-acetylation of host proteins using gnotobiotic mice.
G. M. Simon, J. Cheng, and J. I. Gordon (2012)
PNAS 109, 11133-11138
   Abstract »    Full Text »    PDF »
ALPHARMA BEEF CATTLE NUTRITION SYMPOSIUM: Nutrition and the genome.
H. L. Neibergs and K. A. Johnson (2012)
J Anim Sci 90, 2308-2316
   Abstract »    Full Text »    PDF »
Environmental Triggers of Type 1 Diabetes.
M. Knip and O. Simell (2012)
Cold Spring Harb Perspect Med 2, a007690
   Abstract »    Full Text »    PDF »
Interactions Between the Microbiota and the Immune System.
L. V. Hooper, D. R. Littman, and A. J. Macpherson (2012)
Science 336, 1268-1273
   Abstract »    Full Text »    PDF »
Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.
S. L. Russell, M. J. Gold, M. Hartmann, B. P. Willing, L. Thorson, M. Wlodarska, N. Gill, M.-R. Blanchet, W. W. Mohn, K. M. McNagny, et al. (2012)
EMBO Rep. 13, 440-447
   Abstract »    Full Text »    PDF »
Significance of the microbiome in obstructive lung disease.
M. K. Han, Y. J. Huang, J. J. LiPuma, H. A. Boushey, R. C. Boucher, W. O. Cookson, J. L. Curtis, J. Erb-Downward, S. V. Lynch, S. Sethi, et al. (2012)
Thorax 67, 456-463
   Abstract »    Full Text »    PDF »
Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells.
P. Konieczna, D. Groeger, M. Ziegler, R. Frei, R. Ferstl, F. Shanahan, E. M. M. Quigley, B. Kiely, C. A. Akdis, and L. O'Mahony (2012)
Gut 61, 354-366
   Abstract »    Full Text »    PDF »
Bacillus subtilis-Mediated Protection from Citrobacter rodentium-Associated Enteric Disease Requires espH and Functional Flagella.
S. E. Jones and K. L. Knight (2012)
Infect. Immun. 80, 710-719
   Abstract »    Full Text »    PDF »
Loss of Immunological Tolerance in Gimap5-Deficient Mice Is Associated with Loss of Foxo in CD4+ T Cells.
H. I. Aksoylar, K. Lampe, M. J. Barnes, D. R. Plas, and K. Hoebe (2012)
J. Immunol. 188, 146-154
   Abstract »    Full Text »    PDF »
Tregs and infections: on the potential value of modifying their function.
S. Sehrawat and B. T. Rouse (2011)
J. Leukoc. Biol. 90, 1079-1087
   Abstract »    Full Text »    PDF »
Correlation between Protection against Sepsis by Probiotic Therapy and Stimulation of a Novel Bacterial Phylotype.
J. Gerritsen, H. M. Timmerman, S. Fuentes, L. P. van Minnen, H. Panneman, S. R. Konstantinov, F. M. Rombouts, H. G. Gooszen, L. M. A. Akkermans, H. Smidt, et al. (2011)
Appl. Envir. Microbiol. 77, 7749-7756
   Abstract »    Full Text »    PDF »
The Antibacterial Lectin RegIII{gamma} Promotes the Spatial Segregation of Microbiota and Host in the Intestine.
S. Vaishnava, M. Yamamoto, K. M. Severson, K. A. Ruhn, X. Yu, O. Koren, R. Ley, E. K. Wakeland, and L. V. Hooper (2011)
Science 334, 255-258
   Abstract »    Full Text »    PDF »
Why HLA-B27? My Thirty-Year Quest: The Friedenwald Lecture.
J. T. Rosenbaum (2011)
Invest. Ophthalmol. Vis. Sci. 52, 7712-7715
   Full Text »    PDF »
Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance.
A. R. Kendal, Y. Chen, F. S. Regateiro, J. Ma, E. Adams, S. P. Cobbold, S. Hori, and H. Waldmann (2011)
J. Exp. Med. 208, 2043-2053
   Abstract »    Full Text »    PDF »
Novel Highly Sensitive IL-10-{beta}-Lactamase Reporter Mouse Reveals Cells of the Innate Immune System as a Substantial Source of IL-10 In Vivo.
H. Bouabe, Y. Liu, M. Moser, M. R. Bosl, and J. Heesemann (2011)
J. Immunol. 187, 3165-3176
   Abstract »    Full Text »    PDF »
Mechanisms controlling Th17 cytokine expression and host defense.
J. P. McAleer and J. K. Kolls (2011)
J. Leukoc. Biol. 90, 263-270
   Abstract »    Full Text »    PDF »
Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice.
M. A. Kriegel, E. Sefik, J. A. Hill, H.-J. Wu, C. Benoist, and D. Mathis (2011)
PNAS 108, 11548-11553
   Abstract »    Full Text »    PDF »
A cluster of coregulated genes determines TGF-{beta}-induced regulatory T-cell (Treg) dysfunction in NOD mice.
A. M. D'Alise, A. Ergun, J. A. Hill, D. Mathis, and C. Benoist (2011)
PNAS 108, 8737-8742
   Abstract »    Full Text »    PDF »
The Toll-Like Receptor 2 Pathway Establishes Colonization by a Commensal of the Human Microbiota.
J. L. Round, S. M. Lee, J. Li, G. Tran, B. Jabri, T. A. Chatila, and S. K. Mazmanian (2011)
Science 332, 974-977
   Abstract »    Full Text »    PDF »
Essential role of peripheral node addressin in lymphocyte homing to nasal-associated lymphoid tissues and allergic immune responses.
Y. Ohmichi, J. Hirakawa, Y. Imai, M. Fukuda, and H. Kawashima (2011)
J. Exp. Med. 208, 1015-1025
   Abstract »    Full Text »    PDF »
The Gut's Clostridium Cocktail.
M. J. Barnes and F. Powrie (2011)
Science 331, 289-290
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882