[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses

Nature Immunology volume 8, pages 1086–1094 (2007)Cite this article

Abstract

The intestinal immune system must elicit robust immunity against harmful pathogens but must also restrain immune responses directed against commensal microbes and dietary antigens. The mechanisms that maintain this dichotomy are poorly understood. Here we describe a population of CD11b+F4/80+CD11c− macrophages in the lamina propria that expressed several anti-inflammatory molecules, including interleukin 10 (IL-10), but little or no proinflammatory cytokines, even after stimulation with Toll-like receptor ligands. These macrophages induced, by a mechanism dependent on IL-10, retinoic acid and exogenous transforming growth factor-β, the differentiation of Foxp3+ regulatory T cells. In contrast, lamina propria CD11b+ dendritic cells elicited IL-17 production. This IL-17 production was suppressed by lamina propria macrophages, indicating that a dynamic interaction between these subsets may influence the balance between immune activation and tolerance.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phenotype, morphology and microenvironmental location of lamina propria macrophages.
Figure 2: Lamina propria macrophages have an anti-inflammatory gene expression 'signature'.
Figure 3: Lamina propria macrophages spontaneously secrete IL-10 and are hyporesponsive to TLR stimulation.
Figure 4: IL-10 derived from lamina propria macrophages inhibits the TH1 polarization of CD4+ T cells.
Figure 5: Induction of Foxp3+ Treg cells by lamina propria macrophages but not by DCs.
Figure 6: OT-II T cell cytokine production induced by lamina propria macrophages and DCs.
Figure 7: Intestinal DC subsets differentially generate IL-17-producing T cells.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Pulendran, B. et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl. Acad. Sci. USA 96, 1036–1041 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Maldonado-Lopez, R. et al. CD8α+ and CD8α− subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587–592 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rissoan, M.C. et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183–1186 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Groux, H., Fournier, N. & Cottrez, F. Role of dendritic cells in the generation of regulatory T cells. Semin. Immunol. 16, 99–106 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Pulendran, B. Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol. Rev. 199, 227–250 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Pavli, P., Woodhams, C.E., Doe, W.F. & Hume, D.A. Isolation and characterization of antigen-presenting dendritic cells from the mouse intestinal lamina propria. Immunology 70, 40–47 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Kelsall, B.L. & Rescigno, M. Mucosal dendritic cells in immunity and inflammation. Nat. Immunol. 5, 1091–1095 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Schenk, M. & Mueller, C. Adaptations of intestinal macrophages to an antigen-rich environment. Semin. Immunol. 19, 84–93 (2006).

    Article  PubMed  Google Scholar 

  13. 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 

  14. 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 

  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. Mowat, A.M. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–341 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Kelsall, B.L. & Strober, W. Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch. J. Exp. Med. 183, 237–247 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. 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 

  21. Mora, J.R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Stagg, A.J., Kamm, M.A. & Knight, S.C. Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur. J. Immunol. 32, 1445–1454 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. 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 

  25. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2, 361–367 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. 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 

  28. Maraskovsky, E. et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med. 184, 1953–1962 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Johansson-Lindbom, B. & Agace, W.W. Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol. Rev. 215, 226–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Hume, D.A., Robinson, A.P., MacPherson, G.G. & Gordon, S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Relationship between macrophages, Langerhans cells, reticular cells, and dendritic cells in lymphoid and hematopoietic organs. J. Exp. Med. 158, 1522–1536 (1983).

    Article  CAS  PubMed  Google Scholar 

  32. Freeman, G.J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Benson, M.J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R.J. All-trans retinoic acid mediates enhanced Treg 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 

  35. Sun, C.M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. 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 

  38. Qualls, J.E., Kaplan, A.M., van Rooijen, N. & Cohen, D.A. Suppression of experimental colitis by intestinal mononuclear phagocytes. J. Leukoc. Biol. 80, 802–815 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. Ehirchiou, D. et al. CD11b facilitates the development of peripheral tolerance by suppressing Th17 differentiation. J. Exp. Med. 204, 1519–1524 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kunkel, E.J. & Butcher, E.C. Chemokines and the tissue-specific migration of lymphocytes. Immunity 16, 1–4 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Zabel, B.A. et al. Human G protein-coupled receptor GPR-9–6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190, 1241–1256 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Gorelik, L. & Flavell, R.A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Barnard, J.A., Warwick, G.J. & Gold, L.I. Localization of transforming growth factor β isoforms in the normal murine small intestine and colon. Gastroenterology 105, 67–73 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat. Med. 6, 583–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Mosmann, T.R. & Moore, K.W. The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol. Today 12, A49–A53 (1991).

    Article  CAS  PubMed  Google Scholar 

  54. Fiorentino, D.F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146, 3444–3451 (1991).

    CAS  PubMed  Google Scholar 

  55. Laouar, A. et al. CD70+ antigen-presenting cells control the proliferation and differentiation of T cells in the intestinal mucosa. Nat. Immunol. 6, 698–706 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Hulsey and S. Aguilar Mertens for assistance with cell sorting; T. Querec for assistance with gene array data analysis; R. Mittler (Emory University School of Medicine) for recombinant Flt3 ligand; A. Garcia for electron microscopy; M. Heffernan, S. Pai Kasturi and N. Murthy for synthesis of clodronate liposomes; W. Cao for genotyping CD11cDTR mice; and R. Ahmed (Emory University School of Medicine) and A. Sharpe (Harvard Medical School) for PD-L1 deficient mice. Supported by the National Institutes of Health (AI0564499, AI048638, AI05726601, DK057665, AI057157 and AI-50019 to B.P.; and DK007771-06A1 (Pathobiology of Mucosal/Epithelial Disease) to T.L.D.) and the Crohn's and Colitis Foundation of America (T.L.D.).

Author information

Authors and Affiliations

  1. Vaccine Research Center and Yerkes Regional Primate Research Center, Emory University, Atlanta, 30329, Georgia, USA

    Timothy L Denning, Yi-chong Wang & Bali Pulendran

  2. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, 30322, Georgia, USA

    Seema R Patel, Ifor R Williams & Bali Pulendran

Authors
  1. Timothy L Denning
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-chong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seema R Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ifor R Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bali Pulendran
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.L.D. and B.P. designed the experiments; T.L.D. did the experiments; Y.W., S.R.P. and I.R.W. did the immunohistology; and T.L.D. and B.P. wrote the manuscript.

Corresponding author

Correspondence to Bali Pulendran.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Table 1 and Methods (PDF 2303 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Denning, T., Wang, Yc., Patel, S. et al. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses. Nat Immunol 8, 1086–1094 (2007). https://doi.org/10.1038/ni1511

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1511

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing