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:

IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium

Nature Immunology volume 12, pages 941–948 (2011)Cite this article

Subjects

Abstract

Colonic patches (CLPs) and isolated lymphoid follicles (ILFs) are two main lymphoid structures in the colon. Lymphoid tissue–inducer cells (LTi cells) are indispensable for the development of ILFs. LTi cells also produce interleukin 17 (IL-17) and IL-22, signature cytokines secreted by IL-17-producing helper T cells. Here we report that IL-22 acted downstream of the lymphotoxin pathway and regulated the organization and maintenance of mature CLPs and ILFs in the colon during infection with Citrobacter rodentium. Lymphotoxin (LTα1β2) regulated the production of IL-22 during infection with C. rodentium, but the lymphotoxin-like protein LIGHT did not. IL-22 signaling was sufficient to restore the organization of CLPs and ILFs and host defense against infection with C. rodentium in mice lacking lymphotoxin signals, which suggests that IL-22 connects the lymphotoxin pathway to mucosal epithelial defense mechanisms.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Blockade of lymphotoxin signaling affects CLP and ILF structure in colons from mice infected with C. rodentium.
Figure 2: Blockade of the lymphotoxin pathway inhibits IL-22 expression in colons of mice infected with C. rodentium.
Figure 3: Exogenous IL-23 restores IL-22 induction and host defense during infection with C. rodentium when the lymphotoxin pathway is blocked.
Figure 4: Normal lymphoid structure development in IL-22-deficient mice.
Figure 5: IL-22 blockade disrupts the normal organization of CLPs and ILFs during infection with C. rodentium.
Figure 6: IL-22–Fc rescues mice treated with LTβR-Fc during infection with C. rodentium.
Figure 7: IL-22–Fc restores the structure of CLPs and ILFs in colons of mice treated LTβR-Fc during infection with C. rodentium.

Similar content being viewed by others

References

  1. Newberry, R.D. & Lorenz, R.G. Organizing a mucosal defense. Immunol. Rev. 206, 6–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Randall, T.D., Carragher, D.M. & Rangel-Moreno, J. Development of secondary lymphoid organs. Annu. Rev. Immunol. 26, 627–650 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Taylor, R.T. & Williams, I.R. Lymphoid organogenesis in the intestine. Immunol. Res. 33, 167–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Lorenz, R.G., Chaplin, D.D., McDonald, K.G., McDonough, J.S. & Newberry, R.D. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin β receptor, and TNF receptor I function. J. Immunol. 170, 5475–5482 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Dohi, T. et al. Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2-type responses. J. Exp. Med. 189, 1169–1180 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dohi, T. et al. Elimination of colonic patches with lymphotoxin β receptor-Ig prevents Th2 cell-type colitis. J. Immunol. 167, 2781–2790 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Lee, A.Y. et al. Dendritic cells in colonic patches and iliac lymph nodes are essential in mucosal IgA induction following intrarectal administration via CCR7 interaction. Eur. J. Immunol. 38, 1127–1137 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

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

    Article  CAS  PubMed  Google Scholar 

  10. Eberl, G. & Littman, D.R. Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells. Science 305, 248–251 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Saenz, S.A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Drayton, D.L., Liao, S., Mounzer, R.H. & Ruddle, N.H. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Lügering, A. & Kucharzik, T. Induction of intestinal lymphoid tissue: the role of cryptopatches. Ann. NY Acad. Sci. 1072, 210–217 (2006).

    Article  PubMed  Google Scholar 

  19. 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 

  20. Taylor, R.T., Lugering, A., Newell, K.A. & Williams, I.R. Intestinal cryptopatch formation in mice requires lymphotoxin alpha and the lymphotoxin β receptor. J. Immunol. 173, 7183–7189 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Gommerman, J.L. & Browning, J.L. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3, 642–655 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Ware, C.F. Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23, 787–819 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Wang, Y. et al. Lymphotoxin β receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32, 403–413 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 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 

  26. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Ouyang, W., Rutz, S., Crellin, N.K., Valdez, P.A. & Hymowitz, S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Sa, S.M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Mundy, R., MacDonald, T.T., Dougan, G., Frankel, G. & Wiles, S. Citrobacter rodentium of mice and man. Cell Microbiol. 7, 1697–1706 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. McDonald, K.G., McDonough, J.S. & Newberry, R.D. Adaptive immune responses are dispensable for isolated lymphoid follicle formation: antigen-naive, lymphotoxin-sufficient B lymphocytes drive the formation of mature isolated lymphoid follicles. J. Immunol. 174, 5720–5728 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Spahn, T.W. et al. The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentium-induced colitis. Gastroenterology 127, 1463–1473 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Alimzhanov, M.B. et al. Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice. Proc. Natl. Acad. Sci. USA 94, 9302–9307 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tamada, K. et al. Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGHT. J. Immunol. 168, 4832–4835 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Marchesi, F. et al. CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal Immunol. 2, 486–494 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Zenewicz, L.A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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 

  45. Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Hsu, H.C. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Wong, K. et al. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proc. Natl. Acad. Sci. (USA) 107, 8712–8717 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Ding for generating all plasmids used; R. Alvarado for help with the collection of colons, enzyme-linked immunosorbent assays and RT-PCR analyses; J. Eastham-Anderson for help with imaging on the Ariol SL-50; D. Yan and J. Zhang for technical assistance with gavage; J. Zavala-Solorio for colon photographs; N. Ghilardi (Genentech) for the plasmid expressing IL-23; Y.-X. Fu and Y. Wang (University of Chicago) for LTβ- and LIGHT-deficient mice and analysis of those mice; and F. Martin and M. Balazs for suggestions and discussions.

Author information

Author notes

  1. Patricia A Valdez, Yan Zheng & Natasha K Crellin

    Present address: Present addresses: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA (P.A.V.), Target Discovery & Validation, Novo Nordisk Inflammation Research Center, Seattle, Washington, USA (Y.Z.) and Centers for Therapeutic Innovation–San Francisco, Pfizer, San Francisco, California, USA (N.K.C.).,

  2. Naruhisa Ota, Kit Wong and Patricia A Valdez: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Genentech, South San Francisco, California, USA

    Naruhisa Ota, Kit Wong, Patricia A Valdez, Yan Zheng, Natasha K Crellin & Wenjun Ouyang

  2. Department of Pathology, Genentech, South San Francisco, California, USA

    Lauri Diehl

Authors
  1. Naruhisa Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kit Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patricia A Valdez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Natasha K Crellin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lauri Diehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenjun Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.O., K.W. and P.A.V. did most of experiments and analyzed the data; Y.Z. contributed to Figure 2; L.D. analyzed the histological results in Figure 6g,h; N.K.C. contributed to Supplementary Figure 3; W.O. devised and planned the project; and W.O., N.O., K.W. and P.A.V. wrote the manuscript.

Corresponding author

Correspondence to Wenjun Ouyang.

Ethics declarations

Competing interests

All authors are employees of Genentech.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Table 1 (PDF 848 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ota, N., Wong, K., Valdez, P. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat Immunol 12, 941–948 (2011). https://doi.org/10.1038/ni.2089

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2089

This article is cited by

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