Article | Published:

Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161

Nature Immunology volume 12, pages 10551062 (2011) | Download Citation

Abstract

Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127+CD161+ ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2+ ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2+ ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (TH2) cytokines.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    , & Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair? Nat. Rev. Immunol. 9, 229–234 (2009).

  3. 3.

    & The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011).

  4. 4.

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

  5. 5.

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

  6. 6.

    , , , & CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 10.

    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).

  11. 11.

    et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

  12. 12.

    , & Expansion of human NK-22 cells with IL-7, IL-2, and IL-1b reveals intrinsic functional plasticity. Proc. Natl. Acad. Sci. USA 107, 10961–10966 (2010).

  13. 13.

    et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

    et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).

  20. 20.

    et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995).

  21. 21.

    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).

  22. 22.

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

  23. 23.

    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).

  24. 24.

    , , , & Expression of type 1 (interferon γ) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells. Blood 99, 1273–1281 (2002).

  25. 25.

    et al. Ontogeny of human natural killer (NK) cells: fetal NK cells mediate cytolytic function and express cytoplasmic CD3ɛδ proteins. J. Exp. Med. 175, 1055–1066 (1992).

  26. 26.

    , , , & Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med. 207, 281–290 (2010).

  27. 27.

    et al. T-cell regulation in chronic paranasal sinus disease. J. Allergy Clin. Immunol. 121, 1435–1441 (2008).

  28. 28.

    et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).

  29. 29.

    et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

  30. 30.

    et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J. Clin. Invest. 113, 1490–1497 (2004).

  31. 31.

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

  32. 32.

    & Type 2 innate immune responses and the natural helper cell. Immunology 132, 475–481 (2011).

  33. 33.

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

  34. 34.

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

  35. 35.

    et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).

  36. 36.

    , , , & Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nat. Immunol. 10, 864–871 (2009).

  37. 37.

    , , & Bias in the Cq value observed with hydrolysis probe based quantitative PCR can be corrected with the estimated PCR efficiency value. Methods 50, 313–322 (2010).

  38. 38.

    et al. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res. 37, e45 (2009).

Download references

Acknowledgements

We thank B. Hooibrink and J. Cupp and their teams for help with flow cytometry and Luminex assays; W. Ouyang and C. Kaplan for discussions; A. te Velde and C. Ponsioen for help with intestinal tissues; staff of the Bloemenhove clinic in Heemstede, the Netherlands, for fetal tissues; and K. Weijer, A. Voordouw, N. Legrand and B. Olivier for help with processing various tissues.

Author information

Author notes

    • Sara Trifari
    •  & Natasha K Crellin

    Present address: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA (S.T.), and Pfizer at Rinat, San Francisco, California, USA (N.K.C.).

Affiliations

  1. Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Amsterdam, The Netherlands.

    • Jenny M Mjösberg
    • , Charlotte P Peters
    •  & Hergen Spits
  2. Department of Immunology, Genentech, South San Francisco, California, USA.

    • Sara Trifari
    •  & Natasha K Crellin
  3. Department of Otorhinolaryngology, University of Amsterdam, Amsterdam, The Netherlands.

    • Cornelis M van Drunen
    •  & Wytske J Fokkens
  4. Department of Experimental Immunology and Pulmonology of the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • Berber Piet
  5. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Tom Cupedo

Authors

  1. Search for Jenny M Mjösberg in:

  2. Search for Sara Trifari in:

  3. Search for Natasha K Crellin in:

  4. Search for Charlotte P Peters in:

  5. Search for Cornelis M van Drunen in:

  6. Search for Berber Piet in:

  7. Search for Wytske J Fokkens in:

  8. Search for Tom Cupedo in:

  9. Search for Hergen Spits in:

Contributions

J.M.M. designed the study, did experiments, analyzed the data and wrote the manuscript; S.T. designed the study, did experiments, analyzed the data and wrote the manuscript; N.K.C. did experiments and analyzed the data; C.P.P. did experiments, and provided and processed gut tissue; C.M.v.D. and W.J.F. provided inflamed and uninflamed nasal tissue; B.P. provided and processed lung tissue; T.C. designed the study; and H.S. designed the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hergen Spits.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4 and Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.2104

Further reading