Mucosal surfaces of mammals are exquisitely susceptible to colonization by pathogens and are populated by elaborate mucosal-associated lymphoid tissues that are rich in conventional and specialized cells of the innate and adaptive immune system.
All metazoan organisms have evolved a strategic alliance with commensal microorganisms. For example the gastrointestinal tract is heavily populated by commensal communities composed of species from the eukarya, archaea and bacteria. These communities are remarkably diverse and are essential for normal development and metabolism. In addition, recent studies identified alterations in the acquisition or composition of commensals that are associated with susceptibility to multiple metabolic and inflammatory diseases.
Simultaneous exposure to potential pathogens versus innocuous food antigens and beneficial commensal microorganisms creates a unique regulatory challenge for the gut-associated lymphoid tissues.
Intestinal epithelial cells (IECs) provide a crucial physical barrier to potentially invasive pathogens aided by the expression of intercellular tight junctions, an actin-rich brush border and a secreted glycocalyx. IECs also express germ-line encoded innate immune receptors and in vivo studies suggest that IECs routinely recognize and respond to commensal microorganisms in health and disease.
Mammalian IECs and commensal communities exhibit numerous adaptations that facilitate or limit inappropriate immune responses to commensals and thereby maintain symbiosis. These include restricted localization of pattern-recognition receptors on IECs and the capacity of commensals to limit innate immune signalling in host cells.
In addition to innate recognition of commensal microorganisms, IECs can directly regulate the functions of antigen-presenting cells, innate immune cells and lymphocytes in the intestinal microenvironment, suggesting that IECs are an essential lineage in the maintenance of intestinal immune homeostasis via translation of commensal-derived signals to the mucosal immune system.
Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis. This Review discusses recent findings that identify a cardinal role for epithelial cells in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006).
Gill, S. R., et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).
Bouma, G. & Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nature Rev. Immunol. 3, 521–533 (2003).
Macdonald, T. T. & Monteleone, G. Immunity, inflammation, and allergy in the gut. Science 307, 1920–1955 (2005).
Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124, 823–835 (2006).
Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nature Rev. Immunol. 4, 478–485 (2004).
Mowat, A. M. Anatomical basis of tolerance and immunity to intestinal antigens. Nature Rev. Immunol. 3, 331–341 (2003).
Izcue, A., Coombes, J. L. & Powrie, F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006).
Coombes, J. L. & Maloy, K. J. Control of intestinal homeostasis by regulatory T cells and dendritic cells. Semin. Immunol. 19, 116–126 (2007).
Coombes, J. L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nature Rev. Immunol. 8, 435–436 (2008).
Shen, L. & Turner, J. R. Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: tight junction dynamics exposed. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G577–G582 (2006).
Frey, A., et al. Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting. J. Exp. Med. 184, 1045–1059 (1996).
McAuley, J. L., et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J. Clin. Invest. 117, 2313–2324 (2007).
Sansonetti, P. J. War and peace at mucosal surfaces. Nature Rev. Immunol. 4, 953–964 (2004).
Salzman, N. H., Ghosh, D., Huttner, K., Paterson, Y. & Bevins, C. L. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422, 522–526 (2003). This paper demonstrates a critical in vivo role of paneth-cell-derived defensins in intestinal host defence.
Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nature Rev. Immunol. 3, 710–720 (2003).
Agerberth, B. & Gudmundsson, G. H. Host antimicrobial defence peptides in human disease. Curr. Top. Microbiol. Immunol. 306, 67–90 (2006).
Uehara, A., Fujimoto, Y., Fukase, K. & Takada, H. Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol. Immunol. 44, 3100–3111 (2007).
Neutra, M. R. M cells in antigen sampling in mucosal tissues. Curr. Top. Microbiol. Immunol. 236, 17–32 (1999).
Iwasaki, A. Mucosal dendritic cells. Annu. Rev. Immunol. 25, 381–418 (2007).
Rescigno, M., et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361–367 (2001).
Niess, J. H., et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005). Reference 22 shows that a subset of lamina propria DCs express the chemokine receptor CX 3 CR1 allowing formation of transepithelial dendrites that enable the cells to directly sample luminal antigens.
Niess, J. H. & Reinecker, H. C. Lamina propria dendritic cells in the physiology and pathology of the gastrointestinal tract. Curr. Opin. Gastroenterol. 21, 687–691 (2005).
Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).
Chirdo, F. G., Millington, O. R., Beacock-Sharp, H. & Mowat, A. M. Immunomodulatory dendritic cells in intestinal lamina propria. Eur. J. Immunol. 35, 1831–1840 (2005).
Blanas, E., Davey, G. M., Carbone, F. R. & Heath, W. R. A bone marrow-derived APC in the gut-associated lymphoid tissue captures oral antigens and presents them to both CD4+ and CD8+ T cells. J. Immunol. 164, 2890–2896 (2000).
MacPherson, G., et al. Uptake of antigens from the intestine by dendritic cells. Ann. NY Acad. Sci. 1029, 75–82 (2004).
Milling, S. W., Cousins, L. & MacPherson, G. G. How do DCs interact with intestinal antigens? Trends Immunol. 26, 349–352 (2005).
Liu, L. M. & MacPherson, G. G. Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo. J. Exp. Med. 177, 1299–307 (1993).
Qureshi, S. T. & Medzhitov, R. Toll-like receptors and their role in experimental models of microbial infection. Genes Immun. 4, 87–94 (2003).
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
Girardin, S. E., et al. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 300, 1584–1587 (2003).
Philpott, D. J. & Girardin, S. E. The role of Toll-like receptors and Nod proteins in bacterial infection. Mol. Immunol. 41, 1099–1108 (2004).
Fritz, J. H., Ferrero, R. L., Philpott, D. J. & Girardin, S. E. Nod-like proteins in immunity, inflammation and disease. Nature Immunol. 7, 1250–1257 (2006).
Savage, D. C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107–133 (1977).
Hooper, L. V., et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).
Hooper, L. V. & Gordon, J. I. Commensal host-bacterial relationships in the gut. Science 292, 1115–1118 (2001).
Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).
Whitman, W. B., Coleman, D. C. & Wiebe, W. J. Prokaryotes: the unseen majority. Proc. Natl Acad. Sci. USA 95, 6578–6583 (1998).
Eckburg, P. B., et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).
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). Medzhitov and colleagues demonstrate that commensal bacteria are recognized by TLRs under normal steady-state conditions. This interaction has a crucial role in the maintenance of epithelial-cell homeostasis and protection from injury in the intestine.
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).
Guarner, F. & Malagelada, J. R. Gut flora in health and disease. Lancet 361, 512–519 (2003).
Xu, J. & Gordon, J. I. Inaugural Article: Honor thy symbionts. Proc. Natl Acad. Sci. USA 100, 10452–10459 (2003).
Backhed, F., et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
MacDonald, T. T. & Gordon, J. N. Bacterial regulation of intestinal immune responses. Gastroenterol. Clin. North Am. 34, 401–412 (2005).
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).
Sonnenburg, J. L., Angenent, L. T. & Gordon, J. I. Getting a grip on things: how do communities of bacterial symbionts become established in our intestine? Nature Immunol. 5, 569–573 (2004).
Gordon, H. A. Morphological and physiological characterization of germfree life. Ann. NY Acad. Sci. 78, 208–220 (1959).
Umesaki, Y., Setoyama, H., Matsumoto, S. & Okada, Y. Expansion of αβ T-cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology 79, 32–37 (1993).
Helgeland, L., Vaage, J. T., Rolstad, B., Midtvedt, T. & Brandtzaeg, P. Microbial colonization influences composition and T-cell receptor Vβ repertoire of intraepithelial lymphocytes in rat intestine. Immunology 89, 494–501 (1996).
Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).
Treiner, E., et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).
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). This paper shows that during colonization of animals with the commensal B. fragilis , a bacterial polysaccharide is presented by DCs and directs the maturation of the developing immune system.
Ley, R. E., et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005). Gordon and colleagues demonstrate that genetically obese mice exhibit significant alterations in the composition of their commensal flora and suggest that intentional manipulation of community structure may be useful for regulating metabolism in obese individuals.
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Kalliomaki, M., et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J. Allergy Clin. Immunol. 107, 129–134 (2001).
Noverr, M. C. & Huffnagle, G. B. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 12, 562–568 (2004).
Tlaskalova-Hogenova, H., et al. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol. Lett. 93, 97–108 (2004).
de la Cochetiere, M. F., et al. Early intestinal bacterial colonization and necrotizing enterocolitis in premature infants: the putative role of Clostridium. Pediatr. Res. 56, 366–370 (2004).
Ott, S. J., et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 53, 685–693 (2004).
Noverr, M. C. & Huffnagle, G. B. The 'microflora hypothesis' of allergic diseases. Clin. Exp. Allergy 35, 1511–1520 (2005).
De Hertogh, G., et al. Validation of 16S rDNA sequencing in microdissected bowel biopsies from Crohn's disease patients to assess bacterial flora diversity. J. Pathol. 209, 532–539 (2006).
Garrett, W. S., et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).
Ryu, J. H., et al. Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila. Science 319, 777–782 (2008).
Fagarasan, S., et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 298, 1424–1427 (2002). Honjo and collegues show that deficiency in AID results in a significant expansion of anaerobic flora in the small intestine, implicating a role for intestinal B-cell somatic hypermutation in regulating the commensal flora.
Suzuki, K., et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004).
Neal, M. D., et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176, 3070–3079 (2006).
Altier, C. Genetic and environmental control of Salmonella invasion. J. Microbiol. 43, 85–92 (2005).
Guiney, D. G. The role of host cell death in Salmonella infections. Curr. Top. Microbiol. Immunol. 289, 131–150 (2005).
Brown, N. F., et al. Salmonella pathogenicity island 2 is expressed prior to penetrating the intestine. PLoS Pathog. 1, e32 (2005).
Gal-Mor, O. & Finlay, B. B. Pathogenicity islands: a molecular toolbox for bacterial virulence. Cell. Microbiol. 8, 1707–1719 (2006).
Bhavsar, A. P., Guttman, J. A. & Finlay, B. B. Manipulation of host-cell pathways by bacterial pathogens. Nature 449, 827–834 (2007).
Wald, D., et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature Immunol. 4, 920–927 (2003).
Garlanda, C., et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Natl Acad. Sci. USA 101, 3522–3526 (2004).
Garlanda, C., et al. Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res. 67, 6017–6021 (2007).
Xiao, H., et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26, 461–475 (2007).
Schilling, J. D., Martin, S. M., Hung., C. S., Lorenz, R. G. & Hultgren, S. J. Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc. Natl Acad. Sci. USA 100, 4203–4208 (2003).
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).
Lebeis, S. L., Bommarius, B., Parkos, C. A., Sherman, M. A. & Kalman, D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J. Immunol. 179, 566–577 (2007).
Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006, re13 (2006).
Chen, L. W., et al. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nature Med. 9, 575–581 (2003).
Egan, L. J., et al. IkB-kinaseb-dependent NF-κB activation provides radioprotection to the intestinal epithelium. Proc. Natl Acad. Sci. USA 101, 2452–2457 (2004).
Greten, F. R., et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).
Zaph, C., et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007).
Nenci, A., et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007). References 85 and 86 demonstrate an essential role for intestinal epithelial-cell-intrinsic NF-κB activity in regulating intestinal DC responses and susceptibility to spontaneous or infection-induced intestinal inflammation.
Ogura, Y., et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).
Hugot, J. P., et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).
Maeda, S., et al. Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1β processing. Science 307, 734–738 (2005).
Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453–4460 (2005).
Abreu, M. T., et al. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J. Immunol. 167, 1609–1166 (2001).
Melmed, G., et al. Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J. Immunol. 170, 1406–1415 (2003).
Lotz, M., et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203, 973–984 (2006).
Gewirtz, A. T., Navas, T. A., Lyons, S., Godowski, P. J. & Madara, J. L. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167, 1882–1885 (2001).
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).
Rakoff-Nahoum, S., Hao, L. & Medzhitov, R. Role of Toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329 (2006).
Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).
Neish, A. S., et al. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science 289, 1560–1563 (2000). Madara and colleagues demonstrate that prokaryotic determinants from non-virulent bacteria can inhibit polyubiquitylation and subsequent degradation of IκBα that could contribute to immune hyporesponsiveness in the gut.
Tien, M. T., et al. Anti-inflammatory effect of Lactobacillus casei on Shigella-infected human intestinal epithelial cells. J. Immunol. 176, 1228–1237 (2006).
Collier-Hyams, L. S., Sloane, V., Batten, B. C. & Neish, A. S. Cutting edge: bacterial modulation of epithelial signaling via changes in neddylation of cullin-1. J. Immunol. 175, 4194–4198 (2005).
Kelly, D., et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nature Immunol. 5, 104–112 (2004).
Saemann, M. D., et al. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J. 14, 2380–2382 (2000).
Bashir, M. E., Louie, S., Shi, H. N. & Nagler-Anderson, C. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J. Immunol. 172, 6978–6987 (2004).
Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004). Macpherson and Uhr show that intestinal DCs carry live commensal bacteria to the mesenteric lymph nodes where they selectively induce IgA production.
Iwasaki, A. & Kelsall, B. L. Unique functions of CD11b+, CD8α+, and double-negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–4890 (2001).
Kelsall, B. L. & Leon, F. Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol. Rev. 206, 132–148 (2005).
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).
Sato, A. & Iwasaki, A. Peyer's patch dendritic cells as regulators of mucosal adaptive immunity. Cell. Mol. Life Sci. 62, 1333–1338 (2005).
Colonna, M., Pulendran, B. & Iwasaki, A. Dendritic cells at the host-pathogen interface. Nature Immunol. 7, 117–120 (2006).
Rimoldi, M., Chieppa, M., Vulcano, M., Allavena, P. & Rescigno, M. Intestinal epithelial cells control dendritic cell function. Ann. NY Acad. Sci. 1029, 66–74 (2004).
Rimoldi, M., et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nature Immunol. 6, 507–514 (2005). Rescigno and colleagues show that human IECs can induce non-inflammatory DCs in vitro that preferentially promoted T H 2-type cytokine production in T cells and that this pathway is dysregulated in patients with Crohn's disease.
Vallon-Eberhard, A., Landsman, L., Yogev, N., Verrier, B. & Jung, S. Transepithelial pathogen uptake into the small intestinal lamina propria. J. Immunol. 176, 2465–2469 (2006).
Watanabe, N., et al. Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nature Immunol. 5, 426–434 (2004).
Allakhverdi, Z., et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med. 204, 253–258 (2007).
Kato, A., Favoreto, S. Jr, Avila, P. C. & Schleimer, R. P. TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J. Immunol. 179, 1080–1087 (2007).
Bogiatzi, S. I., et al. Cutting Edge: Proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J. Immunol. 178, 3373–3377 (2007).
Li, M., et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc. Natl Acad. Sci. USA 103, 11736–11741 (2006).
Lee, H. C. & Ziegler, S. F. Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB. Proc. Natl Acad. Sci. USA 104, 914–919 (2007).
Bilsborough, J., George, T. C., Norment, A. & Viney, J. L. Mucosal CD8α+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108, 481–492 (2003).
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 promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007). Work from the Belkaid and Powrie laboratories (references 120 and 121) shows that a subset of CD103+ intestinal DCs can promote peripheral conversion of regulatory T cells via a TGFβ and retinoic-acid-dependent mechanism.
Rimoldi, M., et al. Monocyte-derived dendritic cells activated by bacteria or by bacteria-stimulated epithelial cells are functionally different. Blood 106, 2818–2826 (2005).
Soumelis, V., et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nature Immunol. 3, 673–680 (2002).
Yoo, J., et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp. Med. 202, 541–549 (2005).
Zhou, B., et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nature Immunol. 6, 1047–1053 (2005).
Al-Shami, A., Spolski, R., Kelly, J., Keane-Myers, A. & Leonard, W. J. A role for TSLP in the development of inflammation in an asthma model. J. Exp. Med. 202, 829–839 (2005).
Ziegler, S. F. & Liu, Y. J. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nature Immunol. 7, 709–714 (2006).
Liu, Y. J., et al. TSLP: An epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cellmaturation. Annu. Rev. Immunol. 25, 193–219 (2006).
Dignass, A. U. & Podolsky, D. K. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor β. Gastroenterology 105, 1323–1332 (1993).
Brown, S. L., et al. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest. 117, 258–269 (2007).
Kalinski, P., Vieira, P. L., Schuitemaker, J. H., de Jong, E. C. & Kapsenberg, M. L. Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. Blood 97, 3466–3469 (2001).
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).
Fujita, S., et al. Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response. Blood 107, 3656–3664 (2006).
Newberry, R. D., McDonough, J. S., Stenson, W. F. & Lorenz, R. G. Spontaneous and continuous cyclooxygenase-2-dependent prostaglandin E2 production by stromal cells in the murine small intestine lamina propria: directing the tone of the intestinal immune response. J. Immunol. 166, 4465–4472 (2001).
Harris, S. G., Padilla, J., Koumas, L., Ray, D. & Phipps, R. P. Prostaglandins as modulators of immunity. Trends Immunol. 23, 144–150 (2002).
Arvans, D. L., et al. Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins 25 and 72. Am. J. Physiol. Gastrointest Liver Physiol. 288, G696–G704 (2005).
Luo, X., et al. Release of heat shock protein 70 and the effects of extracellular heat shock protein 70 on the production of IL-10 in fibroblast-like synoviocytes. Cell Stress Chaperones 8 April 2008 (PMID:18392950).
Osterloh, A., Veit, A., Gessner, A., Fleischer, B. & Breloer, M. Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12. Int. Immunol. 20, 433–443 (2008).
Laudanski, K., De, A. & Miller-Graziano, C. Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells. Eur. J. Immunol. 37, 2812–2824 (2007).
Dai, J., Liu, B., Cua, D. J. & Li, Z. Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. Eur. J. Immunol. 37, 706–715 (2007).
Xu, W., et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nature Immunol. 8, 294–303 (2007).
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).
Rojas, R. & Apodaca, G. Immunoglobulin transport across polarized epithelial cells. Nature Rev. Mol. Cell Biol. 3, 944–955 (2002).
Woof, J. M. & Mestecky, J. Mucosal immunoglobulins. Immunol. Rev. 206, 64–82 (2005).
Astrakhan, A., et al. Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development. Nature Immunol. 8, 522–531 (2007).
Cerutti, A. The regulation of IgA class switching. Nature Rev. Immunol. 8, 421–434 (2008).
Hershberg, R. M. & Mayer, L. F. Antigen processing and presentation by intestinal epithelial cells — polarity and complexity. Immunol. Today 21, 123–128 (2000).
Bland, P. W. & Warren, L. G. Antigen presentation by epithelial cells of the rat small intestine. I. Kinetics, antigen specificity and blocking by anti-Ia antisera. Immunology 58, 1–7 (1986).
Bland, P. W. Antigen presentation by gut epithelial cells: secretion by rat enterocytes of a factor with IL-1-like activity. Adv. Exp. Med. Biol. 216A, 219–225 (1987).
Kaiserlian, D., Vidal, K. & Revillard, J. P. Murine enterocytes can present soluble antigen to specific class II-restricted CD4+ T cells. Eur. J. Immunol. 19, 1513–1516 (1989).
Bland, P. W. & Whiting, C. V. Induction of MHC class II gene products in rat intestinal epithelium during graft-versus-host disease and effects on the immune function of the epithelium. Immunology 75, 366–371 (1992).
Telega, G. W., Baumgart, D. C. & Carding, S. R. Uptake and presentation of antigen to T cells by primary colonic epithelial cells in normal and diseased states. Gastroenterology 119, 1548–1559 (2000).
Buning, J., et al. Antigen targeting to MHC class II-enriched late endosomes in colonic epithelial cells: trafficking of luminal antigens studied in vivo in Crohn's colitis patients. FASEB J. 20, 359–361 (2006).
Sanderson, I. R., Ouellette, A. J., Carter, E. A., Walker, W. A. & Harmatz, P. R. Differential regulation of B7 mRNA in enterocytes and lymphoid cells. Immunology 79, 434–438 (1993).
Zoetendal, E. G., Akkermans, A. D. & De Vos, W. M. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Appl. Environ. Microbiol. 64, 3854–3859 (1998).
Palmer, C., Bik, E. M., Digiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007). Palmer et al . analyze commensal bacteria in babies over the first year of life and demonstrate that environmental exposures have a major influence on distinctive and dynamic characteristics of the microbial community in individuals.
Harmsen, H. J., et al. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J. Pediatr. Gastroenterol. Nutr. 30, 61–67 (2000).
Favier, C. F., Vaughan, E. E., De Vos, W. M. & Akkermans, A. D. Molecular monitoring of succession of bacterial communities in human neonates. Appl. Environ. Microbiol. 68, 219–226 (2002).
Fanaro, S., Chierici, R., Guerrini, P. & Vigi, V. Intestinal microflora in early infancy: composition and development. Acta Paediatr. 91, S48–S55 (2003).
Hallstrom, M., Eerola, E., Vuento, R., Janas, M. & Tammela, O. Effects of mode of delivery and necrotising enterocolitis on the intestinal microflora in preterm infants. Eur. J. Clin. Microbiol. Infect. Dis. 23, 463–470 (2004).
Penders, J., et al. Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. FEMS Microbiol. Lett. 243, 141–147 (2005).
Penders, J., et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118, 511–521 (2006).
Thanks to all current members of the Artis laboratory for useful discussions and contributions to this manuscript. Work in the laboratory is supported by the US National Institutes of Health (AI61570, AI74878, F31-GM82187, F32-AI72943, T32-AI007532-08, T32-CA09140-30), University of Pennsylvania Center for Infectious Diseases and University Research Fund, The Irvington Institute Fellowship Program of the Cancer Research Institute and The Crohn's and Colitis Foundation of America's William and Shelby Modell Family Foundation Research Award. Apologies to colleagues whose work and publications could not be referenced due to space constraints.
The author declares no competing financial interests.
- Gut-associated lymphoid tissues
(GALTs). Lymphoid structures and aggregates associated with the intestinal mucosa, specifically the tonsils, Peyer's patches, lymphoid follicles, appendix or coecal patch and mesenteric lymph nodes. They are enriched in conventional and unconventional lymphocytes and specialized dendritic-cell and macrophage subsets.
- Immunological hyporesponsiveness
A diminished degree of responsiveness to antigen or other stimulation. It is an active process, not simply a passive lack of response.
- Tight junctions
Specialized intercellular junctions that seal the apical epithelium. They are formed by several proteins including occludin and claudin, in which two plasma membranes form a sealing gasket around a cell (also known as zonula occludens). Tight junctions prevent fluid moving through the intercellular gaps and prevent lateral diffusion of membrane proteins between the apical and basolateral membranes.
- Brush border
The microvilli-covered surface found on the apical surface of epithelial cells that is coated in a rich glycocalyx of mucus and other glycoproteins. The microvilli contain many of the digestive enzymes and transporter systems that are involved in the metabolism and uptake of dietary materials, and provides a large surface area for absorption. Early anatomists noted that this structure appeared very much like the bristles of a paintbrush, hence the name brush borders.
- Goblet cell
A differentiated epithelial cell that secretes mucus.
- Lamina propria
Connective tissue that is found directly under the mucosal epithelial-cell surface of the gastrointestinal tract. It is traversed by blood and lymphoid vessels, physically supports epithelial cells through the basal membrane and is enriched in innate and adaptive immune cells.
- Peyer's patches
Groups of lymphoid nodules identified by Peyer in 1677 that are present in the small intestine (usually the ileum). They occur massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a subepithelial dome area, B-cell follicles and interfollicular T-cell areas.
- Pattern-recognition receptor
(PRR). A receptor that recognizes unique structures that are present at the surface of microorganisms. Signalling through PRRs leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells. The expression of co-stimulatory molecules, together with the presentation of antigenic peptides, by antigen-presenting cells couples innate immune recognition of pathogens with the activation of adaptive immune responses.
The development of new blood vessels from existing blood vessels.
- Adipose tissue
A type of connective tissue that is specialized for the storage of neutral lipids.
- Activation-induced cytidine deaminase
(AID). An RNA-editing enzyme that is necessary for somatic hypermutation and class-switch recombination.
Single-nucleotide differences in the sequence of genes that represent allelic variants. These differences might lead to altered structure and/or altered expression of gene products, ultimately leading to pathology.
The attachment of the small protein ubiquitin to lysine residues that are present in other proteins. This tags these proteins for rapid cellular degradation the proteasome.
About this article
Cite this article
Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 8, 411–420 (2008). https://doi.org/10.1038/nri2316
Translational Medicine Communications (2021)
Short-term physical exercise impacts on the human holobiont obtained by a randomised intervention study
BMC Microbiology (2021)
Dietary sophorolipid accelerates growth by modulation of gut microbiota population and intestinal environments in broiler chickens
Journal of Animal Science and Biotechnology (2021)
Nature Reviews Immunology (2021)
ISME Communications (2021)