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.

Transcription factor RORα is critical for nuocyte development

Abstract

Nuocytes are essential in innate type 2 immunity and contribute to the exacerbation of asthma responses. Here we found that nuocytes arose in the bone marrow and differentiated from common lymphoid progenitors, which indicates they are distinct, previously unknown members of the lymphoid lineage. Nuocytes required interleukin 7 (IL-7), IL-33 and Notch signaling for development in vitro. Pro-T cell progenitors at double-negative stage 1 (DN1) and DN2 maintained nuocyte potential in vitro, although the thymus was not essential for nuocyte development. Notably, the transcription factor RORα was critical for the development of nuocytes and their role in the expulsion of parasitic worms.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Nuocytes are distinct from CLPs.
Figure 2: Notch signaling is essential for the in vitro generation of nuocytes from CLPs.
Figure 3: Progenitor frequencies support the proposal of a lymphoid origin for nuocytes.
Figure 4: Adoptive transfer of CLPs gives rise to nuocytes.
Figure 5: DN1 and DN2 thymocytes retain the plasticity to differentiate into nuocytes.
Figure 6: RORα is required for nuocyte development.
Figure 7: Intrinsic RORα is required for nuocyte development.
Figure 8: Rorasg/sg mice fail to expel N. brasiliensis efficiently.

References

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  3. Neill, D.R. & McKenzie, A.N. Nuocytes and beyond: new insights into helminth expulsion. Trends Parasitol. 27, 214–221 (2011).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  5. 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).

    CAS  Article  Google Scholar 

  6. Barlow, J.L. et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J. Allergy Clin. Immunol. 129, 191–198 (2012).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  8. Fallon, P.G. et al. IL-4 induces characteristic Th2 responses even in the absence of IL-5, IL-9 and IL-13: analysis of functional redundancy using a novel panel of compound cytokine-deficient mice. Immunity 17, 7–17 (2002).

    CAS  Article  Google Scholar 

  9. Grünig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    Article  Google Scholar 

  10. Mjösberg, J.M. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12, 1055–1062 (2011).

    Article  Google Scholar 

  11. Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).

    CAS  Article  Google Scholar 

  12. Wang, Y.H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).

    CAS  Article  Google Scholar 

  13. 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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  15. 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).

    CAS  Article  Google Scholar 

  16. Cupedo, T. 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).

    CAS  Article  Google Scholar 

  17. 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).

    CAS  Article  Google Scholar 

  18. 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).

    CAS  Article  Google Scholar 

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

    CAS  Google Scholar 

  20. Vonarbourg, C. 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).

    CAS  Article  Google Scholar 

  21. Morrison, S.J. & Weissman, I.L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).

    CAS  Article  Google Scholar 

  22. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

    CAS  Article  Google Scholar 

  23. He, Y.W. & Malek, T.R. Interleukin-7 receptor α is essential for the development of γδ+ T cells, but not natural killer cells. J. Exp. Med. 184, 289–293 (1996).

    CAS  Article  Google Scholar 

  24. Peschon, J.J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    CAS  Article  Google Scholar 

  25. Schlenner, S.M. et al. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity 32, 426–436 (2010).

    CAS  Article  Google Scholar 

  26. Karsunky, H., Inlay, M.A., Serwold, T., Bhattacharya, D. & Weissman, I.L. Flk2+ common lymphoid progenitors possess equivalent differentiation potential for the B and T lineages. Blood 111, 5562–5570 (2008).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  28. Schmitt, T.M. & Zuniga-Pflucker, J.C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    CAS  Article  Google Scholar 

  29. Franco, C.B., Chen, C.C., Drukker, M., Weissman, I.L. & Galli, S.J. Distinguishing mast cell and granulocyte differentiation at the single-cell level. Cell Stem Cell 6, 361–368 (2010).

    CAS  Article  Google Scholar 

  30. Radtke, F., Wilson, A., Mancini, S.J. & MacDonald, H.R. Notch regulation of lymphocyte development and function. Nat. Immunol. 5, 247–253 (2004).

    CAS  Article  Google Scholar 

  31. Rothenberg, E.V., Moore, J.E. & Yui, M.A. Launching the T-cell-lineage developmental programme. Nat. Rev. Immunol. 8, 9–21 (2008).

    CAS  Article  Google Scholar 

  32. Yang, X.O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    CAS  Article  Google Scholar 

  33. Hamilton, B.A. et al. Disruption of the nuclear hormone receptor RORα in staggerer mice. Nature 379, 736–739 (1996).

    CAS  Article  Google Scholar 

  34. Dzhagalov, I., Giguere, V. & He, Y.W. Lymphocyte development and function in the absence of retinoic acid-related orphan receptor α. J. Immunol. 173, 2952–2959 (2004).

    CAS  Article  Google Scholar 

  35. Radtke, F., Fasnacht, N. & Macdonald, H.R. Notch signaling in the immune system. Immunity 32, 14–27 (2010).

    CAS  Article  Google Scholar 

  36. Maillard, I. et al. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2, 356–366 (2008).

    CAS  Article  Google Scholar 

  37. Han, H. et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14, 637–645 (2002).

    CAS  Article  Google Scholar 

  38. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558 (1999).

    CAS  Article  Google Scholar 

  39. Feyerabend, T.B. et al. Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 30, 67–79 (2009).

    CAS  Article  Google Scholar 

  40. Wada, H. et al. Adult T-cell progenitors retain myeloid potential. Nature 452, 768–772 (2008).

    CAS  Article  Google Scholar 

  41. Hozumi, K. et al. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205, 2507–2513 (2008).

    CAS  Article  Google Scholar 

  42. Koch, U. et al. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205, 2515–2523 (2008).

    CAS  Article  Google Scholar 

  43. Amsen, D. et al. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515–526 (2004).

    CAS  Article  Google Scholar 

  44. Tanigaki, K. et al. Regulation of αβ/γδ T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity 20, 611–622 (2004).

    CAS  Article  Google Scholar 

  45. Okamoto, M. et al. Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. J. Immunol. 183, 2995–3003 (2009).

    CAS  Article  Google Scholar 

  46. Possot, C. et al. Notch signaling is necessary for adult, but not fetal, development of RORγt+ innate lymphoid cells. Nat. Immunol. 12, 949–958 (2011).

    CAS  Article  Google Scholar 

  47. Spits, H. & Di Santo, J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011).

    CAS  Article  Google Scholar 

  48. Moffatt, M.F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    CAS  Article  Google Scholar 

  49. Jaradat, M. et al. Modulatory role for retinoid-related orphan receptor α in allergen-induced lung inflammation. Am. J. Respir. Crit. Care Med. 174, 1299–1309 (2006).

    CAS  Article  Google Scholar 

  50. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank S. Bell for critical reading of the manuscript; A. Corcoran (Babraham Institute) for IL-7Rα-deficient mice; M. Turner and E. Vigorito (Babraham Institute) for B6/SJL mice; J.C. Zuniga-Pflucker (University of Toronto) for OP9-DL1 cells; T. Honjo (Kyoto University) for mice with loxP-flanked alleles encoding Rbpjκ; M. Daly for flow cytometry and J. Cruickshank and the staff of the animal facility for experimental support. Supported by Centocor (S.H.W., J.L.B. and A.N.J.M.), the American Asthma Foundation (J.A.W.), Science Foundation Ireland (P.G.F.), the National Children's Research Centre (P.G.F.), the Medical Research Council (A.N.J.M.) and the American Asthma Foundation (A.N.J.M.).

Author information

Authors and Affiliations

Authors

Contributions

A.N.J.M., S.H.W. and J.A.W. conceived of the study; S.H.W., J.A.W., H.E.J., L.F.D., A.C., V.P., J.L.B., D.R.N., Y.Y.H., C.S.H., E.H., U.K. and P.G.F. did the experiments and contributed to experimental design and analysis; F.R. provided reagents and A.N.J.M. wrote the manuscript with contributions from all authors.

Corresponding author

Correspondence to Andrew N J McKenzie.

Ethics declarations

Competing interests

S.H.W., J.L.B. and A.N.J.M. received support from Centocor.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 9170 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wong, S., Walker, J., Jolin, H. et al. Transcription factor RORα is critical for nuocyte development. Nat Immunol 13, 229–236 (2012). https://doi.org/10.1038/ni.2208

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2208

Further reading

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