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.

IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

This article has been updated

Abstract

CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections1. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders2. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing TH2 cell-dependent inflammation at mucosal sites3,4,5,6, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL25, a member of the IL17 cytokine family, promotes the accumulation of a lineage-negative (Lin-) multipotent progenitor (MPP) cell population in the gut-associated lymphoid tissue that promotes TH2 cytokine responses. The IL25-elicited cell population, termed MPPtype2 cells, was defined by the expression of Sca-1 (also known as Ly6a) and intermediate expression of c-Kit (c-Kitint), and exhibited multipotent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPPtype2 cells were competent antigen presenting cells, and adoptive transfer of MPPtype2 cells could promote TH2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il25-/- mice. The ability of IL25 to induce the emergence of an MPPtype2 cell population identifies a link between the IL17 cytokine family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes TH2 cytokine responses at mucosal sites.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: IL25 elicits a c-Kitint-GFP- and c-Kitint-GFP+ cell population in the GALT.
Figure 2: IL25-elicited c-Kitint cells promote TH2 cytokine-dependent responses in vivo.
Figure 3: IL25-elicited c-Kitint cells show multipotent capacity.
Figure 4: Progeny from IL25-elicited c-Kitint-GFP- cells promote TH2 cell differentiation.

Change history

  • 07 March 2010

    The X-axis label for Fig. 1b was moved to horizontal and an extra line was removed from Fig. 4b on 7 March 2010.

References

  1. Anthony, R. M., Rutitzky, L. I., Urban, J. F., Stadecker, M. J. & Gause, W. C. Protective immune mechanisms in helminth infection. Nature Rev. Immunol. 7, 975–987 (2007)

    Article  CAS  Google Scholar 

  2. Umetsu, D. T., McIntire, J. J., Akbari, O., Macaubas, C. & DeKruyff, R. H. Asthma: an epidemic of dysregulated immunity. Nature Immunol. 3, 715–720 (2002)

    Article  CAS  Google Scholar 

  3. Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nature Immunol. 3, 673–680 (2002)

    Article  CAS  Google Scholar 

  4. Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005)

    Article  CAS  Google Scholar 

  5. Fort, M. M. et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo . Immunity 15, 985–995 (2001)

    Article  CAS  Google Scholar 

  6. Zaph, C. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Terashima, A. et al. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J. Exp. Med. 205, 2727–2733 (2008)

    Article  CAS  Google Scholar 

  8. Sokol, C. L., Barton, G. M., Farr, A. G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunol. 9, 310–318 (2008)

    Article  CAS  Google Scholar 

  9. Gessner, A., Mohrs, K. & Mohrs, M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J. Immunol. 174, 1063–1072 (2005)

    Article  CAS  Google Scholar 

  10. Min, B. et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med. 200, 507–517 (2004)

    Article  CAS  Google Scholar 

  11. Voehringer, D., Reese, T. A., Huang, X., Shinkai, K. & Locksley, R. M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203, 1435–1446 (2006)

    Article  CAS  Google Scholar 

  12. Saenz, S. A., Taylor, B. C. & Artis, D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol. Rev. 226, 172–190 (2008)

    Article  CAS  Google Scholar 

  13. Kondo, Y. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol. 20, 791–800 (2008)

    Article  CAS  Google Scholar 

  14. Perrigoue, J. G. et al. MHC class II-dependent basophil-CD4+ T cell interactions promote TH2 cytokine-dependent immunity. Nature Immunol. 10, 697–705 (2009)

    Article  CAS  Google Scholar 

  15. Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2009)

    Article  ADS  Google Scholar 

  16. Fallon, P. G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006)

    Article  CAS  Google Scholar 

  17. Nagai, Y. et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24, 801–812 (2006)

    Article  CAS  Google Scholar 

  18. Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007)

    Article  CAS  Google Scholar 

  19. Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R. M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001)

    Article  CAS  Google Scholar 

  20. Lyon, M. F. & Glenister, P. H. A new allele sash (Wsh) at the W-locus and a spontaneous recessive lethal in mice. Genet. Res. 39, 315–322 (1982)

    Article  CAS  Google Scholar 

  21. Hurst, S. D. et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169, 443–453 (2002)

    Article  CAS  Google Scholar 

  22. Owyang, A. M. et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J. Exp. Med. 203, 843–849 (2006)

    Article  Google Scholar 

  23. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)

    Article  ADS  CAS  Google Scholar 

  24. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008)

    Article  CAS  Google Scholar 

  25. Goodman, J. W. & Hodgson, G. S. Evidence for stem cells in the peripheral blood of mice. Blood 19, 702–714 (1962)

    Article  CAS  Google Scholar 

  26. Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001)

    Article  ADS  CAS  Google Scholar 

  27. Cardier, J. E. & Barbera-Guillem, E. Extramedullary hematopoiesis in the adult mouse liver is associated with specific hepatic sinusoidal endothelial cells. Hepatology 26, 165–175 (1997)

    Article  CAS  Google Scholar 

  28. McKinney-Freeman, S. L. et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl Acad. Sci. USA 99, 1341–1346 (2002)

    Article  ADS  CAS  Google Scholar 

  29. Nakano, T., Kodama, H. & Honjo, T. Generation of lymphohematopoietic cells from embryonic stem cells in culture. Science 265, 1098–1101 (1994)

    Article  ADS  CAS  Google Scholar 

  30. Bell, J. J. & Bhandoola, A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 452, 764–767 (2008)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of the Artis laboratory for constructive discussions, M. Abt, D. Hill, G. Sonnenberg, P. Giacomin, M. Nair and K. Walsh for critical reading of the manuscript, and T. Chi and J. J. Bell for invaluable assistance with reagents and experimental design. Work in the Artis laboratory is supported by the National Institutes of Health (AI61570, AI074878 and AI083480 to D.A., F31 training grant GM082187 to S.A.S., and T32 training grant AI007532-08 to J.G.P.), the Burroughs Wellcome Fund (to D.A.), a National Institute of Diabetes and Digestive Kidney Disease Center Grant (P30 DK50306) and pilot grants from the University of Pennsylvania (URF, VCID and PGI) (to D.A.).

Author information

Authors and Affiliations

Authors

Contributions

S.A.S., M.C.S., J.G.P., S.P.S., T.K., A.B. and D.A. designed and performed the research. J.F.U., J.E.T., A.L.B., M.A.K. and R.A.K. provided new reagents. S.A.S., M.C.S., J.G.P. and D.A. analysed the data. S.A.S. and D.A. wrote the paper.

Corresponding author

Correspondence to David Artis.

Ethics declarations

Competing interests

J.E.T. and A.L.B. are stockholding employees of Amgen. M.A.K. and R.A.K. are employees of SPB, a subsidiary of Merck&Co.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1–13 with legends. (PDF 3428 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Saenz, S., Siracusa, M., Perrigoue, J. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010). https://doi.org/10.1038/nature08901

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08901

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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