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The microbiota in adaptive immune homeostasis and disease
Naturevolume 535, pages75–84 (2016)Cite this article
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Abstract
In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of the barrier functions of the gut mucosa. Imbalances in the gut microbiota, known as dysbiosis, can trigger several immune disorders through the activity of T cells that are both near to and distant from the site of their induction. Elucidation of the mechanisms that distinguish between homeostatic and pathogenic microbiota–host interactions could identify therapeutic targets for preventing or modulating inflammatory diseases and for boosting the efficacy of cancer immunotherapy.
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References
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria.Cell139, 485–498 (2009).Together with ref. 50, this study shows that a subset of the microbiota specifically affects the accumulation of TH17 cells in the intestine.
Wu, H.-J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.Immunity32, 815–827 (2010).
Sivan, A. et al. CommensalBifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science350, 1084–1089 (2015).Together with refs 125 and 126, this study shows that a subset of the microbiota can have an effect on the efficacy of cancer therapy.
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.Nature500, 232–236 (2013).This study and ref. 5 show that a rationally selected consortium of bacteria can specifically induce Treg cells in the intestine that function in systemic immune regulation.
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenousClostridium species.Science331, 337–341 (2011).
Kau, A. L. et al. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy.Sci. Transl. Med.7, 276ra24 (2015).Together with refs 7 and 8, this study shows that IgA-SEQ is a powerful technique for identifying taxa that provide a strong stimulus to the host's immune system.
Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease.Cell158, 1000–1010 (2014).
Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A.Immunity43, 541–553 (2015).
Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice.Nature532, 512–516 (2016).
Roche, A. M., Richard, A. L., Rahkola, J. T., Janoff, E. N. & Weiser, J. N. Antibody blocks acquisition of bacterial colonization through agglutination.Mucosal Immunol.8, 176–185 (2015).
Pabst, O. New concepts in the generation and functions of IgA.Nature Rev. Immunol.12, 821–832 (2012).
Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon, J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis.Cell Host Microbe2, 328–339 (2007).
Cullender, T. C. et al. Innate and adaptive immunity interact to quench microbiome flagellar motility in the gut.Cell Host Microbe14, 571–581 (2013).
Kawamoto, S. et al. Foxp3+ T cells regulate immunoglobulin A selection and facilitate diversification of bacterial species responsible for immune homeostasis.Immunity41, 152–165 (2014).
Friman, V., Nowrouzian, F., Adlerberth, I. & Wold, A. E. Increased frequency of intestinalEscherichia coli carrying genes for S fimbriae and haemolysin in IgA-deficient individuals.Microb. Pathog.32, 35–42 (2002).
Wei, M. et al. Mice carrying a knock-in mutation ofAicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense.Nature Immunol.12, 264–270 (2011).
Moon, C. et al. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation.Nature521, 90–93 (2015).
Kubinak, J. L. et al. MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health.Cell Host Microbe17, 153–163 (2015).
Hirota, K. et al. Plasticity of TH17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses.Nature Immunol.14, 372–379 (2013).
Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses.Science328, 1705–1709 (2010).
Lindner, C. et al. Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota.Nature Immunol.16, 880–888 (2015).
Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells.Cell126, 1121–1133 (2006).
Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine.Cell Host Microbe4, 337–349 (2008).
Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation.Nature455, 808–812 (2008).
Weaver, C. T., Elson, C. O., Fouser, L. A. & Kolls, J. K. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin.Annu. Rev. Pathol.8, 477–512 (2013).
Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.Science332, 65–68 (2011).
Okada, S. et al. Impairment of immunity toCandida andMycobacterium in humans with bi-allelicRORC mutations.Science349, 606–613 (2015).
Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses.Immunity30, 108–119 (2009).
McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cellsin vivo.Nature Immunol.10, 314–324 (2009).
Coccia, M. et al. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells.J. Exp. Med.209, 1595–1609 (2012).
Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses.Nature Immunol.12, 255–263 (2011).
El-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.Nature Immunol.12, 568–575 (2011).
Harbour, S. N., Maynard, C. L., Zindl, C. L., Schoeb, T. R. & Weaver, C. T. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis.Proc. Natl Acad. Sci. USA112, 7061–7066 (2015).
Ahern, P. P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells.Immunity33, 279–288 (2010).
Jain, R. et al. Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells.Immunity44, 131–142 (2016).
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.Nature496, 513–517 (2013).
Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.Nature496, 518–522 (2013).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science341, 569–573 (2013).Together with refs 39–41, this study identified short-chain fatty acids as strong inducers of Treg cells in the colon.
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.Nature504, 446–450 (2013).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.Nature504, 451–455 (2013).
Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine.Immunity43, 817–829 (2015).
Berod, L. et al.De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells.Nature Med.20, 1327–1333 (2014).
Santori, F. R. et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells.Cell Metab.21, 286–297 (2015).
Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity.Cell163, 1413–1427 (2015).
Naik, S. et al. Compartmentalized control of skin immunity by resident commensals.Science337, 1115–1119 (2012).
Umesaki, Y., Setoyama, H., Matsumoto, S., Imaoka, A. & Itoh, K. Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system.Infect. Immun.67, 3504–3511 (1999).
Lécuyer, E. et al. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses.Immunity40, 608–620 (2014).
Goto, Y. et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation.Science345, 1254009 (2014).
Prakash, T. et al. Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of Th17 cell differentiation.Cell Host Microbe10, 273–284 (2011).
Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells.Cell163, 367–380 (2015).Together with ref. 51, this study shows that the response of intestinal TH17 cells is directed towards commensal and pathogenic bacteria that activate epithelial cells.
Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses.Cell163, 381–393 (2015); erratum164, 324 (2016).
Schnupf, P. et al. Growth and host interaction of mouse segmented filamentous bacteriain vitro.Nature520, 99–103 (2015).
Panea, C. et al. Intestinal monocyte-derived macrophages control commensal-specific Th17 responses.Cell Rep.12, 1314–1324 (2015).
Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine.Immunity35, 780–791 (2011).
Persson, E. K. et al. IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation.Immunity38, 958–969 (2013).
Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses.Immunity38, 970–983 (2013).
Derebe, M. G. et al. Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection.eLife3, e03206 (2014).
Sczesnak, A. et al. The genome of Th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment.Cell Host Microbe10, 260–272 (2011).
Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens.Nature510, 152–156 (2014).This study and ref. 122 show that different constituents of the microbiota guide distinct pathways of T-cell differentiation that is specific for the antigens of commensal bacteria.
Block, K. E., Zheng, Z., Dent, A. L., Kee, B. L. & Huang, H. Gut microbiota regulates K/BxN autoimmune arthritis through follicular helper T but not Th17 cells.J. Immunol.196, 1550–1557 (2016).
Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis.Proc. Natl Acad. Sci. USA108 (suppl. 1), 4615–4622 (2011).
Kriegel, M. A. et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice.Proc. Natl Acad. Sci. USA108, 11548–11553 (2011).
Fransen, F. et al. BALB/c and C57BL/6 mice differ in polyreactive IgA abundance, which impacts the generation of antigen-specific IgA and microbiota diversity.Immunity43, 527–540 (2015).
Morton, A. M. et al. Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut.Proc. Natl Acad. Sci. USA111, 6696–6701 (2014).
Horai, R. et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site.Immunity43, 343–353 (2015).
Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination.Nature479, 538–541 (2011).
Harkiolaki, M. et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides.Immunity30, 348–357 (2009).
Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of theZAP-70 gene causes autoimmune arthritis in mice.Nature426, 454–460 (2003).
Hepworth, M. R. et al. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells.Science348, 1031–1035 (2015).
Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota.Proc. Natl Acad. Sci. USA107, 12204–12209 (2010).
Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses.Immunity34, 794–806 (2011).
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, 1723–1742 (2012).
Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization.Proc. Natl Acad. Sci. USA111, 13145–13150 (2014).
Bilate, A. M. & Lafaille, J. J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance.Annu. Rev. Immunol.30, 733–758 (2012).
Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function.Annu. Rev. Immunol.30, 531–564 (2012).
Kim, S. V. et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa.Science340, 1456–1459 (2013).
Ohnmacht, C. et al. The microbiota regulates type 2 immunity through RORγt+ T cells.Science349, 989–993 (2015).Together with refs 78 and 79, this study shows that a subset of Treg cells in the intestine express RORγt and that their development is affected by the microbiota.
Sefik, E. et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells.Science349, 993–997 (2015).
Yang, B. H. et al. Foxp3 T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation.Mucosal Immunol.9, 444–457 (2016).
Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota.Nature478, 250–254 (2011).
Roers, A. et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation.J. Exp. Med.200, 1289–1297 (2004).
Krause, P. et al. IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis.Nature Commun.6, 7055 (2015).
Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces.Immunity28, 546–558 (2008).
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.Immunity34, 554–565 (2011).
Park, S. G. et al. T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells.Immunity33, 791–803 (2010).
Gagliani, N. et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation.Nature523, 221–225 (2015).
Wohlfert, E. A. et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice.J. Clin. Invest.121, 4503–4515 (2011).
Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine.Nature513, 564–568 (2014).
Kim, K. S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine.Science351, 858–863 (2016).
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).
Mathewson, N. D. et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.Nature Immunol.17, 505–513 (2016).
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. USA105, 16731–16736 (2008).
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).
Reis, B. S., Rogoz, A., Costa-Pinto, F. A., Taniuchi, I. & Mucida, D. Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity.Nature Immunol.14, 271–280 (2013).
Mucida, D. et al. Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes.Nature Immunol.14, 281–289 (2013).
Narushima, S. et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia.Gut Microbes5, 333–339 (2014).
Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis.Immunity40, 128–139 (2014).
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 TGF-β-bearing regulatory cells.J. Immunol.174, 3237–3246 (2005).
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).
Tang, C. et al. Inhibition of Dectin-1 signaling ameliorates colitis by inducingLactobacillus-mediated regulatory T cell expansion in the intestine.Cell Host Microbe18, 183–197 (2015).
Kullberg, M. C. et al. Bacteria-triggered CD4+ T regulatory cells suppressHelicobacter hepaticus-induced colitis.J. Exp. Med.196, 505–515 (2002).
Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection.Cell Host Microbe12, 509–520 (2012).
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).
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).
Sun, C. M. et al. Small intestine lamina propria dendritic cells promotede novo generation of Foxp3 T reg cells via retinoic acid.J. Exp. Med.204, 1775–1785 (2007).
Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis.Science343, 1249288 (2014).
Loschko, J. et al. Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation.J. Exp. Med.213, 517–534 (2016).
Stary, G. et al. A mucosal vaccine againstChlamydia trachomatis generates two waves of protective memory T cells.Science348, aaa8205 (2015).
Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function.Science336, 489–493 (2012).
Scharschmidt, T. C. et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes.Immunity43, 1011–1021 (2015).
Russell, S. L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.EMBO Rep.13, 440–447 (2012).
Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation.Nature Med.18, 538–546 (2012).
Cahenzli, J., Koller, Y., Wyss, M., Geuking, M. B. & McCoy, K. D. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels.Cell Host Microbe14, 559–570 (2013).
Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma.Sci. Transl. Med.7, 307ra152 (2015).
Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis inIl10−/− mice.Nature487, 104–108 (2012).
Small, C. L., Reid-Yu, S. A., McPhee, J. B. & Coombes, B. K. Persistent infection with Crohn's disease-associated adherent-invasiveEscherichia coli leads to chronic inflammation and intestinal fibrosis.Nature Commun.4, 1957 (2013).
Frank, D. N. et al. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.Inflamm. Bowel Dis.17, 179–184 (2011).
Ramanan, D., Tang, M. S., Bowcutt, R., Loke, P. & Cadwell, K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensalBacteroides vulgatus.Immunity41, 311–324 (2014).
Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn's disease.Cell Host Microbe15, 382–392 (2014).
Scher, J. U. et al. Expansion of intestinalPrevotella copri correlates with enhanced susceptibility to arthritis.eLife2, e01202 (2013).
Vujkovic-Cvijin, I. et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism.Sci. Transl. Med.5, 193ra91 (2013).
Hand, T. W. et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses.Science337, 1553–1556 (2012).
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. USA106, 19256–19261 (2009).
Lodes, M. J. et al. Bacterial flagellin is a dominant antigen in Crohn disease.J. Clin. Invest.113, 1296–1306 (2004).
Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide.Science342, 971–976 (2013).
Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science350, 1079–1084 (2015).
Charbonneau, M. R. et al. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition.Cell164, 859–871 (2016).
Cao, A. T. et al. Interleukin (IL)-21 promotes intestinal IgA response to microbiota.Mucosal Immunol.8, 1072–1082 (2015).
Kruglov, A. A. et al. Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis.Science342, 1243–1246 (2013).
Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut.Immunity34, 122–134 (2011).
Longman, R. S. et al. CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.J. Exp. Med.211, 1571–1583 (2014).
Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease geneAtg16L1 phenotypes in intestine.Cell141, 1135–1145 (2010).
Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria.Nature516, 94–98 (2014).
Naik, S. et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature520, 104–108 (2015).
Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection.Proc. Natl Acad. Sci. USA108, 5354–5359 (2011).
Acknowledgements
This work was supported by: grants from the Japan Agency for Medical Research and Development (AMED) and the Takeda Science Foundation (K.H.); US National Institutes of Health grant RO1DK103358 and the Howard Hughes Medical Institute (D.R.L.).
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Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan
Kenya Honda
RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan
Kenya Honda
AMED-CREST, Chiyoda, Tokyo, 100-0004, Japan
Kenya Honda
The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, 10016, New York, USA
Dan R. Littman
The Howard Hughes Medical Institute, New York University School of Medicine, New York, 10016, New York, USA
Dan R. Littman
- Kenya Honda
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Correspondence toKenya Honda orDan R. Littman.
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The authors are scientific co-founders and consultants for Vedanta Biosciences, which specializes in microbiome-based therapeutics.
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Honda, K., Littman, D. The microbiota in adaptive immune homeostasis and disease.Nature535, 75–84 (2016). https://doi.org/10.1038/nature18848
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