Hill, D. A. & Artis, D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu. Rev. Immunol.28, 623–667 (2010). CASPubMedPubMed Central Google Scholar
Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nature Rev. Immunol.8, 411–420 (2008). CAS Google Scholar
Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev. Immunol.10, 159–169 (2010). CAS Google Scholar
Koslowski, M. J., Beisner, J., Stange, E. F. & Wehkamp, J. Innate antimicrobial host defense in small intestinal Crohn's disease. Int. J. Med. Microbiol.300, 34–40 (2010). CASPubMed 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. USA105, 20858–20863 (2008). ADSCASPubMedPubMed Central Google Scholar
Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature456, 259–263 (2008). ADSCASPubMedPubMed Central Google Scholar
Kaser, A., Martinez-Naves, E. & Blumberg, R. S. Endoplasmic reticulum stress: implications for inflammatory bowel disease pathogenesis. Curr. Opin. Gastroenterol.26, 318–326 (2010). CASPubMedPubMed Central Google Scholar
Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell134, 743–756 (2008). This report links ER stress in IECs to the development of intestinal inflammation in both mice and humans. CASPubMedPubMed Central Google Scholar
Taylor, B. C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med.206, 655–667 (2009). CASPubMedPubMed Central Google Scholar
Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Rev. Immunol.10, 131–144 (2010). CAS Google Scholar
Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol.28, 243–273 (2010). CASPubMed Google Scholar
Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science325, 617–620 (2009). ADSCASPubMedPubMed Central Google Scholar
Asquith, M. J., Boulard, O., Powrie, F. & Maloy, K. J. Pathogenic and protective roles of MyD88 in leukocytes and epithelial cells in mouse models of inflammatory bowel disease. Gastroenterology139, 519–529 (2010). CASPubMed Google Scholar
Cario, E. Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm. Bowel Dis.16, 1583–1597 (2010). PubMed Google Scholar
Strober, W., Murray, P. J., Kitani, A. & Watanabe, T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nature Rev. Immunol.6, 9–20 (2006). CAS Google Scholar
Chen, G. Y., Shaw, M. H., Redondo, G. & Nunez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res.68, 10060–10067 (2008). CASPubMedPubMed Central Google Scholar
Dupaul-Chicoine, J. et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity32, 367–378 (2010). CASPubMed Google Scholar
Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity32, 379–391 (2010). CASPubMedPubMed Central Google Scholar
Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med.207, 1045–1056 (2010). CASPubMedPubMed Central Google Scholar
Siegmund, B. Interleukin-18 in intestinal inflammation: friend and foe? Immunity32, 300–302 (2010). CASPubMed Google Scholar
Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med.207, 1625–1636 (2010). CASPubMedPubMed Central Google Scholar
Feng, T., Wang, L., Schoeb, T. R., Elson, C. O. & Cong, Y. Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis. J. Exp. Med.207, 1321–1332 (2010). CASPubMedPubMed Central Google Scholar
Asquith, M. & Powrie, F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J. Exp. Med.207, 1573–1577 (2010). CASPubMedPubMed Central Google Scholar
Saleh, M. & Trinchieri, G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nature Rev. Immunol.11, 9–20 (2011). CAS Google Scholar
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). ADSCASPubMedPubMed Central Google Scholar
Richardson, W. M. et al. Nucleotide-binding oligomerization domain-2 inhibits Toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology139, 904–917 (2010). CASPubMed Google Scholar
Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nature Immunol.11, 55–62 (2010). CAS Google Scholar
Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med.16, 90–97 (2010). CASPubMed Google Scholar
Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature456, 264–268 (2008). References 31 and 32 describe a link between key Crohn's disease susceptibility factors by showing that NOD2 can stimulate autophagy and that this constitutes an important bacterial handling mechanism. ADSCASPubMed Google Scholar
Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature469, 221–225 (2011). ADSCASPubMed Google Scholar
Martinon, F., Chen, X., Lee, A. H. & Glimcher, L. H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nature Immunol.11, 411–418 (2010). CAS Google Scholar
Melmed, G. Y. & Targan, S. R. Future biologic targets for IBD: potentials and pitfalls. Nature Rev. Gastroenterol. Hepatol.7, 110–117 (2010). Google Scholar
Maloy, K. J. & Kullberg, M. C. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol.1, 339–349 (2008). CASPubMed Google Scholar
Kamada, N. et al. Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest.118, 2269–2280 (2008). CASPubMedPubMed Central Google Scholar
Goodall, J. C. et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc. Natl Acad. Sci. USA107, 17698–17703 (2010). ADSCASPubMedPubMed Central Google Scholar
Ahern, P. P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity33, 279–288 (2010). CASPubMedPubMed Central Google Scholar
Leppkes, M. et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology136, 257–267 (2009). CASPubMed Google Scholar
Cosmi, L. et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med.205, 1903–1916 (2008). CASPubMedPubMed Central Google Scholar
Kleinschek, M. A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med.206, 525–534 (2009). CASPubMedPubMed Central Google Scholar
Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science326, 986–991 (2009). ADSCASPubMedPubMed Central Google Scholar
Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature464, 1371–1375 (2010). ADSCASPubMedPubMed Central Google Scholar
Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Med.15, 1016–1022 (2009). CASPubMed Google Scholar
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell139, 485–498 (2009). CASPubMedPubMed Central Google Scholar
Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity31, 677–689 (2009). References 47 and 48 document a strong link between segmented filamentous bacteria colonization and TH17 cells and, together with reference 80, provide compelling evidence that colonization with distinct types of commensal bacterium results in the accumulation of different effector T cells in the intestine. CASPubMed Google Scholar
Wolk, K., Witte, E., Witte, K., Warszawska, K. & Sabat, R. Biology of interleukin-22. Semin. Immunopathol.32, 17–31 (2010). CASPubMed Google Scholar
Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med.206, 1465–1472 (2009). CASPubMedPubMed Central Google Scholar
Sonnenberg, G. F. et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med.207, 1293–1305 (2010). CASPubMedPubMed Central Google Scholar
Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity30, 576–587 (2009). CASPubMedPubMed Central Google Scholar
Ng, J. et al. Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology139, 542–552.e3 (2010). CASPubMed Google Scholar
Muller, A. J. et al. The S. Typhimurium effector SopE induces caspase-1 activation in stromal cells to initiate gut inflammation. Cell Host Microbe6, 125–136 (2009). CASPubMed Google Scholar
Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity31, 15–23 (2009). CASPubMed Google Scholar
Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nature Rev. Immunol.10, 479–489 (2010). CAS Google Scholar
Park, S. G. et al. T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells. Immunity33, 791–803 (2010). CASPubMedPubMed Central Google Scholar
Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity31, 321–330 (2009). CASPubMed Google Scholar
Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity31, 331–341 (2009). CASPubMed Google Scholar
Spits, H. & Di Santo, J. P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nature Immunol.12, 21–27 (2011). CAS Google Scholar
Sawa, S. et al. Lineage relationship analysis of RORγ+ innate lymphoid cells. Science330, 665–669 (2010). ADSCASPubMed Google Scholar
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). References 45 and 62 identify new populations of LTI-like ILCs that secrete TH1 and TH17 pro-inflammatory cytokines in response to IL-23, and these contribute to intestinal pathology and host defences against intestinal pathogenic bacteria. CASPubMed Google Scholar
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature463, 540–544 (2010). ADSCASPubMed Google Scholar
Saenz, S. A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature464, 1362–1366 (2010). ADSCASPubMedPubMed Central Google Scholar
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature464, 1367–1370 (2010). References 63–65 describe various ILC populations that secrete TH2 cytokines (ILC type 2) in response to IL-25 and IL-33 and that can contribute to defence against intestinal helminth infection. ADSCASPubMedPubMed Central Google Scholar
Coombes, J. L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nature Rev. Immunol.8, 435–446 (2008). CAS Google Scholar
Varol, C., Zigmond, E. & Jung, S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nature Rev. Immunol.10, 415–426 (2010). CAS Google Scholar
Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity31, 502–512 (2009). CASPubMed Google Scholar
Schulz, O. et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med.206, 3101–3114 (2009). CASPubMedPubMed Central Google Scholar
Niess, J. H. & Adler, G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J. Immunol.184, 2026–2037 (2010). CASPubMed Google Scholar
Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science329, 849–853 (2010). ADSCASPubMedPubMed Central Google Scholar
Laffont, S., Siddiqui, K. R. & Powrie, F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur. J. Immunol.40, 1877–1883 (2010). CASPubMedPubMed Central Google Scholar
Smith, P. D. et al. Intestinal macrophages and response to microbial encroachment. Mucosal Immunol.4, 31–42 (2011). PubMed Google Scholar
Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nature Immunol.10, 1178–1184 (2009). CAS Google Scholar
Hadis, U. et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity34, 237–246 (2011). This study shows that oral tolerance requires homing and expansion of Tregcells in the intestine. CASPubMed Google Scholar
Siddiqui, K. R., Laffont, S. & Powrie, F. E-cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity32, 557–567 (2010). CASPubMedPubMed Central Google Scholar
Platt, A. M., Bain, C. C., Bordon, Y., Sester, D. P. & Mowat, A. M. An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J. Immunol.184, 6843–6854 (2010). CASPubMed Google Scholar
Izcue, A., Coombes, J. L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol.27, 313–338 (2009). CASPubMed Google Scholar
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science331, 337–341 (2011). This paper describes a link betweenClostridiumspp. and Tregcells in the gut and, together with references 47 and 48, provides compelling evidence that colonization with distinct commensal bacteria results in the accumulation of different effector T cells in the intestine. ADSCASPubMed Google Scholar
Littman, D. R. & Rudensky, A. Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell140, 845–858 (2010). CASPubMed Google Scholar
Hall, J. A. et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity29, 637–649 (2008). CASPubMedPubMed Central Google Scholar
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). CASPubMedPubMed Central Google Scholar
Oldenhove, G. et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity31, 772–786 (2009). CASPubMedPubMed Central Google Scholar
Li, M. O. & Flavell, R. A. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity28, 468–476 (2008). PubMed Google Scholar
Fantini, M. C. et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology136, 1308–1316.e3 (2009). CASPubMed Google Scholar
Pesu, M. et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature455, 246–250 (2008). ADSCASPubMedPubMed Central Google Scholar
Perruche, S. et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells. Nature Med.14, 528–535 (2008). CASPubMed Google Scholar
Torchinsky, M. B., Garaude, J., Martin, A. P. & Blander, J. M. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature458, 78–82 (2009). ADSCASPubMed Google Scholar
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). ADSCASPubMedPubMed Central Google Scholar
Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nature Rev. Immunol.10, 170–181 (2010). CAS Google Scholar
Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med.361, 2033–2045 (2009). CASPubMedPubMed Central Google Scholar
Smith, A. M. et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J. Exp. Med.206, 1883–1897 (2009). CASPubMedPubMed Central Google Scholar
Sartor, R. B. Microbial influences in inflammatory bowel diseases. Gastroenterology134, 577–594 (2008). CASPubMed Google Scholar
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). PubMed Google Scholar
Willing, B. P. et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology139, 1844–1854.e1 (2010). PubMed Google Scholar
Maslowski, K. M. & Mackay, C. R. Diet, gut microbiota and immune responses. Nature Immunol.12, 5–9 (2011). CAS Google Scholar
Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell141, 1135–1145 (2010). CASPubMedPubMed Central Google Scholar
Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe8, 292–300 (2010). References 99 and 100 provide illustrative examples of how several host and environmental factors may act together to precipitate chronic intestinal inflammation. CASPubMedPubMed Central Google Scholar