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Dendritic cells in intestinal immune regulation

Nature Reviews Immunology volume 8, pages 435–446 (2008)Cite this article

Key Points

  • An important feature of the intestinal immune system is its ability to protect against infection while avoiding the development of destructive inflammatory responses to the normal microbiota and dietary antigens.

  • Populations of intestinal dendritic cells (DCs) display unique functional properties. They have been implicated both in the maintenance of tolerance towards harmless antigens, and in the generation of protective immune responses against pathogens.

  • Recent data suggests that intestinal DCs can promote differentiation of forkhead box P3 (FOXP3)+ regulatory T cells from naive precursors. Transforming growth factor-β and retinoic acid have an important role in this process.

  • Conditioning of DCs in their local tissue environment may have an important role in shaping their function.

  • A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease. Inappropriate or aberrant DC function may have a role in the pathogenesis of inflammatory bowel disease.

Abstract

A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease, coeliac disease and allergy. Dendritic cells, through their ability to orchestrate protective immunity and immune tolerance in the host, have a key role in shaping the intestinal immune response. The mechanisms through which dendritic cells can respond to environmental cues in the intestine and select appropriate immune responses have until recently been poorly understood. Here, we review recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine.

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Figure 1: Role of vitamin A metabolites in intestinal DC function.
Figure 2: Conditioning of DCs in the intestine.
Figure 3: Response of intestinal DCs to infection.

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References

  1. Iwasaki, A. Mucosal dendritic cells. Annu. Rev. Immunol. 25, 381–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Smith, P. D., Ochsenbauer-Jambor, C. & Smythies, L. E. Intestinal macrophages: unique effector cells of the innate immune system. Immunol. Rev. 206, 149–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Johansson, C. & Kelsall, B. L. Phenotype and function of intestinal dendritic cells. Semin. Immunol. 17, 284–294 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Iwasaki, A. & Kelsall, B. L. Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J. Exp. Med. 190, 229–239 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Iwasaki, A. & Kelsall, B. L. Unique functions of CD11b+, CD8α+, and double-negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–4890 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Annacker, O., et al. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J. Exp. Med. 202, 1051–1061 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Iwasaki, A. & Kelsall, B. L. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–1394 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol. 8, 1086–1094 (2007).

    Article  CAS  Google Scholar 

  11. Naik, S. H., et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nature Immunol. 7, 663–671 (2006).

    Article  CAS  Google Scholar 

  12. Wilson, N. S., et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102, 2187–2194 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Fogg, D. K., et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Varol, C., et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171–180 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Yrlid, U., Jenkins, C. D. & MacPherson, G. G. Relationships between distinct blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under steady-state conditions. J. Immunol. 176, 4155–4162 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Yoshida, M., et al. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20, 769–783 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Jang, M. H., et al. Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 101, 6110–6115 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. Turnbull, E. L., Yrlid, U., Jenkins, C. D. & Macpherson, G. G. Intestinal dendritic cell subsets: differential effects of systemic TLR4 stimulation on migratory fate and activation in vivo. J. Immunol. 174, 1374–1384 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Wilson, N. S., et al. Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll-like receptor signaling. Immunol. Cell Biol. 86, 200–205 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Huang, F. P., et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–444 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Worbs, T., et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jiang, A., et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007). This study provided details of a distinctive programme of DC maturation initiated by disruption of E-cadherin-mediated DC–DC interactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wendland, M., et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc. Natl Acad. Sci. USA 104, 6347–6352 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yrlid, U., et al. Regulation of intestinal dendritic cell migration and activation by plasmacytoid dendritic cells, TNF-α and type 1 IFNs after feeding a TLR7/8 ligand. J. Immunol. 176, 5205–5212 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mucida, D., et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Yamazaki, S., et al. Dendritic cells are specialized accessory cells along with TGF-β for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3− precursors. Blood 110, 4293–4302 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E. & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724–3733 (2007). These papers, together with reference 10, demonstrated an important role for populations of MLN DCs, lamina propria DCs and lamina propria macrophages in the generation of FOXP3+ T Reg cells from naive peripheral CD4+ T cells. This was found to be mediated in part by retinoic acid, which enhanced TGFβ-mediated induction of FOXP3.

    Article  CAS  PubMed  Google Scholar 

  35. Johansson-Lindbom, B., et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Travis, M. A., et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007). This study provided physiological evidence that DCs, through the activation of TGFβ, can influence intestinal immune homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lacy-Hulbert, A., et al. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc. Natl Acad. Sci. USA 104, 15823–15828 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fahlen, L., et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stagg, A. J., Kamm, M. A. & Knight, S. C. Intestinal dendritic cells increase T cell expression of α4β7 integrin. Eur. J. Immunol. 32, 1445–1454 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Johansson-Lindbom, B., et al. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J. Exp. Med. 198, 963–969 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mora, J. R., et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Briskin, M., et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97–110 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kunkel, E. J., et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192, 761–768 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Siewert, C., et al. Induction of organ-selective CD4+ regulatory T cell homing. Eur. J. Immunol. 37, 978–989 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Macpherson, A. J. & Slack, E. The functional interactions of commensal bacteria with intestinal secretory IgA. Curr. Opin. Gastroenterol. 23, 673–678 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Martinoli, C., Chiavelli, A. & Rescigno, M. Entry route of Salmonella typhimurium directs the type of induced immune response. Immunity 27, 975–984 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Sato, A., et al. CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells. J. Immunol. 171, 3684–3690 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. Cerutti, A. The regulation of IgA class switching. Nature Rev. Immunol. 8, 421–434 (2008).

    Article  CAS  Google Scholar 

  51. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schambach, F., Schupp, M., Lazar, M. A. & Reiner, S. L. Activation of retinoic acid receptor-α favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur. J. Immunol. 37, 2396–2399 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Iwata, M., et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Mora, J. R., et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006). This study showed that gut-associated lymphoid tissue DCs could promote expression of gut-homing receptors by B cells. This was mediated by retinoic acid. Retinoic acid also synergized with IL-5 and IL-6 to promote secretion of IgA.

    Article  CAS  PubMed  Google Scholar 

  55. McDermott, M. R., et al. Impaired intestinal localization of mesenteric lymphoblasts associated with vitamin A deficiency and protein-calorie malnutrition. Immunology 45, 1–5 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Stephensen, C. B. Vitamin A, infection, and immune function. Annu. Rev. Nutr. 21, 167–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Elias, K. M., et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111, 1013–1020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Blomhoff, R. & Blomhoff, H. K. Overview of retinoid metabolism and function. J. Neurobiol. 66, 606–630 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Saurer, L., McCullough, K. C. & Summerfield, A. In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J. Immunol. 179, 3504–3514 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Lampen, A., Meyer, S., Arnhold, T. & Nau, H. Metabolism of vitamin A and its active metabolite all-trans-retinoic acid in small intestinal enterocytes. J. Pharmacol. Exp. Ther. 295, 979–985 (2000).

    CAS  PubMed  Google Scholar 

  61. Svensson, M. e. a. Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells. Mucosal Immunol. 1, 38–48 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cantorna, M. T., Nashold, F. E. & Hayes, C. E. In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J. Immunol. 152, 1515–1522 (1994).

    CAS  PubMed  Google Scholar 

  63. Sidell, N., Chang, B. & Bhatti, L. Upregulation by retinoic acid of interleukin-2-receptor mRNA in human T lymphocytes. Cell. Immunol. 146, 28–37 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Rincon, M. & Flavell, R. A. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J. 13, 4370–4381 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu, Y., et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Schule, R., et al. Retinoic acid is a negative regulator of AP-1-responsive genes. Proc. Natl Acad. Sci. USA 88, 6092–6096 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fantini, M. C., et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Artis, D. Epithelial-cell recognition of commensal flora and maintenance of immune homeostasis in the gut. Nature Rev. Immunol. 8, 411–421 (2008).

    Article  CAS  Google Scholar 

  69. Rimoldi, M., et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nature Immunol. 6, 507–514 (2005). This study emphasised the importance of interactions between epithelial cells and DCs in the regulation of intestinal immune responses. DCs cultured with epithelial-cell supernatants were 'conditioned' to produce less IL-12 and promote T H 2-type responses. This effect was in part mediated by TSLP.

    Article  CAS  Google Scholar 

  70. Zaph, C., et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007). This paper deals with the crosstalk between the intestinal epithelium and DCs. Mice with an IEC-specific deletion of IKKβ have impaired expression of TSLP, which results in elevated production of IL-12/23p40 by DCs and failure to mount protective T H 2-type responses following Trichuris muris infection.

    Article  CAS  PubMed  Google Scholar 

  71. Watanabe, N., et al. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181–1185 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Szatmari, I., et al. PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J. Exp. Med. 203, 2351–2362 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kobayashi, M., et al. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J. Clin. Invest. 111, 1297–1308 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Takeda, K., et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Butler, M., et al. Modulation of dendritic cell phenotype and function in an in vitro model of the intestinal epithelium. Eur. J. Immunol. 36, 864–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Rakoff-Nahoum, S., Hao, L. & Medzhitov, R. Role of Toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. 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 

  78. Contractor, N., Louten, J., Kim, L., Biron, C. A. & Kelsall, B. L. Cutting edge: Peyer's patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: possible role for IL-10, TGFβ, and prostaglandin E2 in conditioning a unique mucosal pDC phenotype. J. Immunol. 179, 2690–2694 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Sierro, F., et al. Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proc. Natl Acad. Sci. USA 98, 13722–13727 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Nenci, A., et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. 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 

  83. Salazar-Gonzalez, R. M., et al. CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches. Immunity 24, 623–632 (2006). This study revealed that T-cell activation following Salmonella spp . infection was dependent on the recruitment of CCR6-expressing DCs to the follicle-associated epithelium of the Peyer's patches.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bettelli, E., et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Hart, A. L., et al. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology 129, 50–65 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Uhlig, H. H., et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Berndt, B. E., Zhang, M., Chen, G. H., Huffnagle, G. B. & Kao, J. Y. The role of dendritic cells in the development of acute dextran sulfate sodium colitis. J. Immunol. 179, 6255–6262 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Abe, K., et al. Conventional dendritic cells regulate the outcome of colonic inflammation independently of T cells. Proc. Natl Acad. Sci. USA 104, 17022–17027 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Watanabe, N., et al. Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice. Dig Dis. Sci. 48, 408–414 (2003).

    Article  PubMed  Google Scholar 

  90. 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).

    Article  CAS  Google Scholar 

  91. 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 

  92. Li, J., et al. Regulation of IL-8 and IL-1β expression in Crohn's disease associated NOD2/CARD15 mutations Hum. Mol. Genet. 13, 1715–1725 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Uehara, A., et al. Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. Cell. Microbiol. 7, 53–61 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Netea, M. G., et al. Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J. Immunol. 174, 6518–6523 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. van Heel, D. A., et al. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet 365, 1794–1796 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. van Beelen, A. J., et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27, 660–669 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Happel, K. I., et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ivanov, I. I., et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Mangan, P. R., et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. 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 

  101. Watanabe, T., et al. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J. Clin. Invest. 118, 545–559 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Watanabe, T., Kitani, A., Murray, P. J. & Strober, W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nature Immunol. 5, 800–808 (2004).

    Article  CAS  Google Scholar 

  103. Maeda, S., et al. Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1β processing. Science 307, 734–738 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Duerr, R. H., et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yen, D., et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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 

  107. 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 

  108. Izcue, A., et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sugimoto, K., et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Jang, M. H., et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Karlis, J., et al. Characterization of colonic and mesenteric lymph node dendritic cell subpopulations in a murine adoptive transfer model of inflammatory bowel disease. Inflamm. Bowel Dis. 10, 834–847 (2004).

    Article  PubMed  Google Scholar 

  112. Liu, L. M. & MacPherson, G. G. Rat intestinal dendritic cells: immunostimulatory potency and phenotypic characterization. Immunology 85, 88–93 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kilshaw, P. J. Expression of the mucosal T cell integrin αM290 β7 by a major subpopulation of dendritic cells in mice. Eur. J. Immunol. 23, 3365–3368 (1993).

    Article  CAS  PubMed  Google Scholar 

  114. Brenan, M. & Puklavec, M. The MRC OX-62 antigen: a useful marker in the purification of rat veiled cells with the biochemical properties of an integrin. J. Exp. Med. 175, 1457–1465 (1992).

    Article  CAS  PubMed  Google Scholar 

  115. Asselin-Paturel, C., Brizard, G., Pin, J. J., Briere, F. & Trinchieri, G. Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody. J. Immunol. 171, 6466–6477 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Yrlid, U., et al. Plasmacytoid dendritic cells do not migrate in intestinal or hepatic lymph. J. Immunol. 177, 6115–6121 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Balmer, J. E. & Blomhoff, R. Gene expression regulation by retinoic acid. J. Lipid Res. 43, 1773–1808 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. La, P., et al. Fusion proteins of retinoid receptors antagonize TGF-b-induced growth inhibition of lung epithelial cells. Oncogene 22, 198–210 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Pendaries, V., Verrecchia, F., Michel, S. & Mauviel, A. Retinoic acid receptors interfere with the TGF-b/Smad signaling pathway in a ligand-specific manner. Oncogene 22, 8212–8220 (2003)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by the Wellcome trust (F.P.), the European Union (Euro-Thymaide FP6 Integrated Project; LSHB-CT-2003-503410), and the Medical Research Council (J.C.).

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

    Janine L. Coombes & Fiona Powrie

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  1. Janine L. Coombes
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Correspondence to Fiona Powrie.

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Glossary

Inflammatory bowel disease

(IBD). A group of conditions, of unknown aetiology, in which the intestinal mucosa is chronically inflammed. Includes Crohn's disease and ulcerative colitis.

Plasmacytoid DC

(pDCs). A subset of dendritic cells (DCs) the microscopic appearance of which resembles plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type I interferons (IFNs) in response to virus infections. Recent studies have identified subsets of type-I-IFN-producing DCs in mice, which are identified by expression of B220, Ly6C and other markers.

M cells

(Microfold cells). Specialized epithelial cells that deliver antigens by transepithelial vesicular transport from the gut lumen directly to intraepithelial lymphocytes and to subepithelial lymphoid tissues.

Regulatory T cell

(TReg cell). A type of CD4+ T cell that is characterized by its expression of forkhead box P3 (FOXP3) and high levels of CD25. TReg cells can downmodulate many types of immune responses. CD4+CD25+FOXP3+ TReg cells that develop in the thymus are exported to the periphery with their regulatory function already intact. However, FOXP3+ T cells with regulatory function can also be generated in the periphery from naive CD4+ T cells following, for example, the oral administration of antigen or targeting of peptide ligands to dendritic cells in vivo.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-6, TGFβ (transforming growth factor-β), IL-23 and IL-21, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

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Coombes, J., Powrie, F. Dendritic cells in intestinal immune regulation. Nat Rev Immunol 8, 435–446 (2008). https://doi.org/10.1038/nri2335

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