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.

  • Progress
  • Published:

Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair?

Nature Reviews Immunology volume 9, pages 229–234 (2009)Cite this article

Abstract

Mucosal tissues, lying at the interface with the external environment, are constantly challenged by microbial, physical and chemical assaults. To provide the necessary immune defence to such challenges, lymph nodes and Peyer's patches are formed in utero in response to inductive signals from lymphoid-tissue inducer (LTi) cells. As discussed in this Progress article, a series of recent reports has identified a population of interleukin-22-producing mucosal cells in the gut and tonsils that share features with both LTi cells (by expressing RORγt) and natural killer cells (by expressing NKp46) and that might be involved in immunity and homeostasis in mucosal tissues.

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

Access options

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: Anatomical localization of gut NK cells and RORγt+NKp46+ cells.
Figure 2: Working models for the developmental relationship between NK cells and LTi cells.

Similar content being viewed by others

References

  1. Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).

    Article  CAS  Google Scholar 

  2. Mebius, R. E., Rennert, P. & Weissman, I. L. Developing lymph nodes collect CD4+CD3−LTβ+ cells that can differentiate to APC, NK cells and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nature Immunol. 5, 64–73 (2004).

    Article  CAS  Google Scholar 

  5. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Kanamori, Y. et al. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+IL-7R+Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med. 184, 1449–1459 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Naito, T., Shiohara, T., Hibi, T., Suematsu, M. & Ishikawa, H. RORγt is dispensable for the development of intestinal mucosal T cells. Mucosal Immunol. 1, 198–207 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Yoshida, H. et al. Expression of α4β7 integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J. Immunol. 167, 2511–2521 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Cupedo, T. et al. Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes. J. Immunol. 173, 2968–2975 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Kim, M. Y. et al. Heterogeneity of lymphoid tissue inducer cell populations present in embryonic and adult mouse lymphoid tissues. Immunology 124, 166–174 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Scandella, E. et al. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nature Immunol. 9, 667–675 (2008).

    Article  CAS  Google Scholar 

  14. Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin-17-producing precursors to RORC+CD127+ natural killer-like cells. Nature Immunol. 10, 66–74 (2009).

    Article  CAS  Google Scholar 

  15. 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 

  16. Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nature Rev. Immunol. 8, 337–348 (2008).

    Article  CAS  Google Scholar 

  17. Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ouyang, W., Kolls, J. K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nature Immunol. 10, 75–82 (2009).

    Article  CAS  Google Scholar 

  20. Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin-22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).

    Article  CAS  Google Scholar 

  21. Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Satoh-Takayama, N. et al. Microbial flora drives interleukin-22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Moretta, A., Biassoni, R., Bottino, C., Mingari, M. C. & Moretta, L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol. Today 21, 228–234 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Moretta, L. & Moretta, A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. Embo J. 23, 255–259 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Mandelboim, O. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Walzer, T., Jaeger, S., Chaix, J. & Vivier, E. Natural killer cells: from CD3−NKp46+ to post-genomics meta-analyses. Curr. Opin. Immunol. 19, 365–372 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Walzer, T. et al. Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc. Natl Acad. Sci. USA 104, 3384–3389 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meresse, B. et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J. Exp. Med. 203, 1343–1355 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vivier, E. & Anfossi, N. Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future. Nature Rev. Immunol. 4, 190–198 (2004).

    Article  CAS  Google Scholar 

  30. Diefenbach, A., Jamieson, A. M., Liu, S. D., Shastri, N. & Raulet, D. H. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunol. 1, 119–126 (2000).

    Article  CAS  Google Scholar 

  31. Jamieson, A. M. et al. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17, 19–29 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Groh, V. et al. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl Acad. Sci. USA 93, 12445–12450 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Diefenbach, A., Jensen, E. R., Jamieson, A. M. & Raulet, D. H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nature Immunol. 9, 503–510 (2008).

    Article  CAS  Google Scholar 

  36. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Casamayor-Palleja, M. et al. Expression of macrophage inflammatory protein-3α, stromal cell-derived factor-1, and B-cell-attracting chemokine-1 identifies the tonsil crypt as an attractive site for B cells. Blood 97, 3992–3994 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Kwon, J. H., Keates, S., Bassani, L., Mayer, L. F. & Keates, A. C. Colonic epithelial cells are a major site of macrophage inflammatory protein 3α (MIP-3α) production in normal colon and inflammatory bowel disease. Gut 51, 818–826 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tanaka, Y. et al. Selective expression of liver and activation-regulated chemokine (LARC) in intestinal epithelium in mice and humans. Eur. J. Immunol. 29, 633–642 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Coles, M. C. et al. Role of T and NK cells and IL7/IL7R interactions during neonatal maturation of lymph nodes. Proc. Natl Acad. Sci. USA 103, 13457–13462 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Freud, A. G. et al. Evidence for discrete stages of human natural killer cell differentiation in vivo. J. Exp. Med. 203, 1033–1043 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Quong, M. W., Romanow, W. J. & Murre, C. E protein function in lymphocyte development. Annu. Rev. Immunol. 20, 301–322 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Boos, M. D., Yokota, Y., Eberl, G. & Kee, B. L. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 204, 1119–1130 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin-15-deficient mice. J. Exp. Med. 191, 771–780 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoshida, H. et al. IL-7 receptor α+ CD3− cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11, 643–655 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Malmberg, K. J. & Ljunggren, H. G. Spotlight on IL-22-producing NK cell receptor-expressing mucosal lymphocytes. Nature Immunol. 10, 11–12 (2009).

    Article  CAS  Google Scholar 

  47. Hughes, T. et al. Stage three immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22. Blood 24 Feb 2009 (doi:10.1182/blood-2008-12-19244).

Download references

Acknowledgements

The Vivier laboratory is supported by the Ligue Nationale contre le Cancer (Equipe labellisée La Ligue), the Agence Nationale de la Recherche, INSERM, CNRS and the Ministère de l'Enseignement Supérieur et de la Recherche. T.C. is supported by an Innovative Research Incentives Scheme VENI grant from the Dutch organization for scientific research (NWO).

Author information

Authors and Affiliations

  1. Eric Vivier is at the Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, INSERM, U631, and Centre National de la Recherche Scientifique, UMR6102, 13288 Marseille, France, and at the Assistance Publique — Hôpitaux de Marseille, Hôpital de la Conception, 13005 Marseille, France.,

    Eric Vivier

  2. Hergen Spits is at Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, USA.,

    Hergen Spits

  3. Department of Hematology, Tom Cupedo is at the Erasmus University Medical Center, Room Ee133Of, PO Box 2040, 3000 CA Rotterdam, the Netherlands.,

    Tom Cupedo

Authors
  1. Eric Vivier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hergen Spits
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tom Cupedo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Eric Vivier, Hergen Spits or Tom Cupedo.

Ethics declarations

Competing interests

Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair? Nature Reviews Immunology 9, 229–234 (2009); doi:10.1038/nri2522

Eric Vivier is a founder of and shareholder in Innate Pharma SA.

Related links

Related links

FURTHER INFORMATION

Eric Vivier's lab

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vivier, E., Spits, H. & Cupedo, T. Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair?. Nat Rev Immunol 9, 229–234 (2009). https://doi.org/10.1038/nri2522

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2522

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