Immune adaptations that maintain homeostasis with the intestinal microbiota (original) (raw)

• Mathers, C. D., Boerma, T. & Ma Fat, D. Global and regional causes of death. Br. Med. Bull. 92, 7–32 (2009).
  Article PubMed Google Scholar
• Xu, J. et al. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).
  Article CAS PubMed Google Scholar
• Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).
  Article CAS PubMed Google Scholar
• Martens, E. C., Chiang, H. C. & Gordon, J. I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nature Rev. Microbiol. 6, 776–788 (2008).
  Article CAS Google Scholar
• Xu, J. & Gordon, J. I. Inaugural article: honor thy symbionts. Proc. Natl Acad. Sci. USA 100, 10452–10459 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001). This paper shows that commensal bacteria manipulate host cell functions and widely influence host biology, revealing the essential nature of the interactions between resident microorganisms and their mammalian hosts.
  Article CAS PubMed Google Scholar
• Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269–273 (2003).
  Article CAS Google Scholar
• Stappenbeck, T. S., Hooper, L. V. & Gordon, J. I. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).
  Article CAS PubMed Google Scholar
• 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 Microbe 4, 337–349 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hall, J. A. et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637–649 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228–3241 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Klare, I., Werner, G. & Witte, W. Enterococci. Habitats, infections, virulence factors, resistances to antibiotics, transfer of resistance determinants. Contrib. Microbiol. 8, 108–122 (2001).
  Article CAS PubMed Google Scholar
• Benson, A., Pifer, R., Behrendt, C. L., Hooper, L. V. & Yarovinsky, F. Gut commensal bacteria direct a protective immune response against Toxoplasma gondii. Cell Host Microbe 6, 187–196 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kuwahara, T. et al. Genomic analysis of Bacteroides fragilis reveals extensive DNA inversions regulating cell surface adaptation. Proc. Natl Acad. Sci. USA 101, 14919–14924 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008). This paper clearly visualizes the spatial relationships between the microbiota and the intestinal epithelial cell surface, and it shows that mucus glycoproteins are essential for limiting direct contact between luminal bacteria and epithelial cells.
  Article CAS PubMed PubMed Central Google Scholar
• Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).
  Article CAS PubMed Google Scholar
• Celli, J. P. et al. Helicobacter pylori moves through mucus by reducing mucin viscoelasticity. Proc. Natl Acad. Sci. USA 106, 14321–14326 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Guerry, P. Campylobacter flagella: not just for motility. Trends Microbiol. 15, 456–461 (2007).
  Article CAS PubMed Google Scholar
• Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
  Article CAS PubMed Google Scholar
• Putsep, K. et al. Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275, 40478–40482 (2000).
  Article CAS PubMed Google Scholar
• Brandl, K., Plitas, G., Schnabl, B., Dematteo, R. P. & Pamer, E. G. MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).
  Article CAS PubMed Google Scholar
• Meyer-Hoffert, U. et al. Secreted enteric antimicrobial activity localizes to the mucus surface layer. Gut 57, 764–771 (2008).
  Article CAS PubMed Google Scholar
• Boneca, I. G. et al. A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system. Proc. Natl Acad. Sci. USA 104, 997–1002 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Guo, L. et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95, 189–198 (1998).
  Article CAS PubMed Google Scholar
• Raffatellu, M. et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5, 476–486 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).
  Article CAS PubMed Google Scholar
• Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004). This study shows that DCs harbouring live commensal bacteria are restricted to the mucosal immune compartment by mesenteric lymph nodes, which thus function as an immune firewall that limits systemic penetration of commensal bacteria.
  Article CAS PubMed Google Scholar
• Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361–367 (2001).
  Article CAS Google Scholar
• Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).
  Article CAS PubMed Google Scholar
• Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003).
  Article CAS Google Scholar
• Lee, S. H., Starkey, P. M. & Gordon, S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J. Exp. Med. 161, 475–489 (1985).
  Article CAS PubMed Google Scholar
• Kelsall, B. Recent progress in understanding the phenotype and function of intestinal dendritic cells and macrophages. Mucosal Immunol. 1, 460–469 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Sansonetti, P. J. War and peace at mucosal surfaces. Nature Rev. Immunol. 4, 953–964 (2004).
  Article CAS Google Scholar
• Macpherson, A. J., Geuking, M. B. & McCoy, K. D. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 115, 153–162 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005).
  Article CAS PubMed Google Scholar
• Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).
  Article CAS PubMed Google Scholar
• Shroff, K. E., Meslin, K. & Cebra, J. J. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect. Immun. 63, 3904–3913 (1995).
  CAS PubMed PubMed Central Google Scholar
• Benveniste, J., Lespinats, G. & Salomon, J. Serum and secretory IgA in axenic and holoxenic mice. J. Immunol. 107, 1656–1662 (1971).
  CAS PubMed Google Scholar
• Guy-Grand, D. et al. Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J. Exp. Med. 173, 471–481 (1991).
  Article CAS PubMed Google Scholar
• Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nature Rev. Immunol. 4, 478–485 (2004).
  Article CAS Google Scholar
• Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009).
  Article CAS PubMed Google Scholar
• Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).
  Article CAS PubMed Google Scholar
• Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396–400 (2008).
  Article CAS PubMed Google Scholar
• Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).
  Article CAS PubMed Google Scholar
• Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Asseman, C., Read, S. & Powrie, F. Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J. Immunol. 171, 971–978 (2003).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Cong, Y., Weaver, C. T., Lazenby, A. & Elson, C. O. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J. Immunol. 169, 6112–6119 (2002).
  Article CAS PubMed Google Scholar
• Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).
  Article CAS PubMed Google Scholar
• Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).
  Article CAS PubMed Google Scholar
• Neurath, M. F. et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J. Exp. Med. 195, 1129–1143 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).
  Article CAS PubMed Google Scholar
• Mazmanian, S. K. & Kasper, D. L. The love–hate relationship between bacterial polysaccharides and the host immune system. Nature Rev. Immunol. 6, 849–858 (2006).
  Article CAS Google Scholar
• Becker, C. et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Gautreaux, M. D., Gelder, F. B., Deitch, E. A. & Berg, R. D. Adoptive transfer of T lymphocytes to T-cell-depleted mice inhibits Escherichia coli translocation from the gastrointestinal tract. Infect. Immun. 63, 3827–3834 (1995).
  CAS PubMed PubMed Central Google Scholar
• Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).
  Article CAS PubMed Google Scholar
• Lee, Y. K., Mukasa, R., Hatton, R. D. & Weaver, C. T. Developmental plasticity of Th17 and Treg cells. Curr. Opin. Immunol. 21, 274–280 (2009).
  Article CAS PubMed Google Scholar
• Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Maloy, K. J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kullberg, M. C. et al. Bacteria-triggered CD4+ T regulatory cells suppress _Helicobacter hepaticus_-induced colitis. J. Exp. Med. 196, 505–515 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Kullberg, M. C. et al. IL-23 plays a key role in _Helicobacter hepaticus_-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Hue, S. et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 266, 1253–1255 (1994).
  Article CAS PubMed Google Scholar
• Chen, Y., Chou, K., Fuchs, E., Havran, W. L. & Boismenu, R. Protection of the intestinal mucosa by intraepithelial γδ T cells. Proc. Natl Acad. Sci. USA 99, 14338–14343 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Groh, V., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998).
  Article CAS PubMed Google Scholar
• Suemizu, H. et al. A basolateral sorting motif in the MICA cytoplasmic tail. Proc. Natl Acad. Sci. USA 99, 2971–2976 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Ismail, A. S., Behrendt, C. L. & Hooper, L. V. Reciprocal interactions between commensal bacteria and γδ intraepithelial lymphocytes during mucosal injury. J. Immunol. 182, 3047–3054 (2009).
  Article CAS PubMed Google Scholar
• Poussier, P., Ning, T., Banerjee, D. & Julius, M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 195, 1491–1497 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).
  Article CAS Google Scholar
• Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).
  Article CAS PubMed Google Scholar
• Shiloh, M. U. et al. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity 10, 29–38 (1999). This study shows the essential role of microbicidal mechanisms in containing the commensal intestinal microbiota.
  Article CAS PubMed Google Scholar
• Sansonetti, P. Phagocytosis of bacterial pathogens: implications in the host response. Semin. Immunol. 13, 381–390 (2001).
  Article CAS PubMed Google Scholar
• Gowans, J. L. & Knight, E. J. The route of re-circulation of lymphocytes in the rat. Proc. R. Soc. Lond. B Biol. Sci. 159, 257–282 (1964).
  Article CAS PubMed Google Scholar
• Husband, A. J. & Gowans, J. L. The origin and antigen-dependent distribution of IgA-containing cells in the intestine. J. Exp. Med. 148, 1146–1160 (1978). This is a landmark study of the immune geography of the mucosal immune system, showing the dissemination of IgA+ plasma cells that have been induced in the intestinal mucosa through the lymph and blood.
  Article CAS PubMed Google Scholar
• Pierce, N. F. & Gowans, J. L. Cellular kinetics of the intestinal immune response to cholera toxoid in rats. J. Exp. Med. 142, 1550–1563 (1975).
  Article CAS PubMed Google Scholar
• Nagl, M. et al. Phagocytosis and killing of bacteria by professional phagocytes and dendritic cells. Clin. Diagn. Lab. Immunol. 9, 1165–1168 (2002).
  PubMed PubMed Central Google Scholar
• Konrad, A., Cong, Y., Duck, W., Borlaza, R. & Elson, C. O. Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology 130, 2050–2059 (2006).
  Article CAS PubMed Google Scholar
• Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Swidsinski, A., Weber, J., Loening-Baucke, V., Hale, L. P. & Lochs, H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J. Clin. Microbiol. 43, 3380–3389 (2005).
  Article PubMed PubMed Central Google Scholar
• Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).
  CAS PubMed Google Scholar
• Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001). References 88 and 89 show that NOD2 polymorphisms account for a proportion of the genetic risk of Crohn's disease. This was the first of a large number of linked genetic loci to be identified and the suspected dysregulation of host–microorganism mutualism as a cause of IBD was reinforced by the finding that NOD2 senses a bacterial cell wall component.
  Article CAS PubMed Google Scholar
• Wehkamp, J. et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc. Natl Acad. Sci. USA 102, 18129–18134 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Garabedian, E. M., Roberts, L. J., McNevin, M. S. & Gordon, J. I. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272, 23729–23740 (1997).
  Article CAS PubMed Google Scholar
• Chapel, H. et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 112, 277–286 (2008).
  Article CAS PubMed Google Scholar
• Notarangelo, L. et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J. Allergy Clin. Immunol. 117, 883–896 (2006).
  Article PubMed Google Scholar
• Casanova, J. L. & Abel, L. Primary immunodeficiencies: a field in its infancy. Science 317, 617–619 (2007).
  Article CAS PubMed Google Scholar
• Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005). This landmark study uses molecular profiling to reveal the diversity of the human microflora and establish the dominant bacterial phylotypes that inhabit the human gastrointestinal tract.
  Article PubMed PubMed Central Google Scholar
• Ogura, Y. et al. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52, 1591–1597 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–5512 (2003).
  Article CAS PubMed Google Scholar