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.

Innate lymphoid cells — a proposal for uniform nomenclature

This article has been updated

Abstract

Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.

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: Classification of ILCs into three groups on the basis of their functional characteristics.

Change history

  • 10 January 2013

    In the original version of this article published online, reference 11 was incorrect. This has now been replaced with the correct reference. The authors apologize for this error. In addition, references 24 and 25 have now been updated.

References

  1. Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Kiessling, R. Klein, E., Pross, H. & Wigzell, H. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur. J. Immunol. 5, 117–121 (1975).

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. 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 

  5. 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 

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

    Article  CAS  Google Scholar 

  7. 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 

  8. 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  PubMed  Google Scholar 

  9. 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 

  10. Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nature Immunol. 12, 1045–1054 (2011).

    CAS  Google Scholar 

  11. Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  13. Hanash, A. M. et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37, 339–350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Halim, T. Y., Krauss, R. H., Sun, A. C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Satoh-Takayama, N. et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med. 207, 273–280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gordon, S. M. et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36, 55–67 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Crellin, N. K., Trifari, S., Kaplan, C. D., Cupedo, T. & Spits, H. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bernink, J. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nature Immunol (in the press).

  25. Klose, C. S. N. et al. A T-bet gradient controls the fate and function of CCR6 RORγt+ innate lymphoid cells. Nature 16 Jan 2013 (doi:10.1038/nature11813).

    Article  CAS  PubMed  Google Scholar 

  26. Powell, N. et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37, 674–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bending, D. et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J. Clin. Invest. 119, 565–572 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mukasa, R. et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32, 616–627 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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  PubMed  Google Scholar 

  31. 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  PubMed  Google Scholar 

  32. 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  PubMed  PubMed Central  Google Scholar 

  33. Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nature Immunol. 12, 1071–1077 (2011).

    Article  CAS  Google Scholar 

  34. Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liang, H. E. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nature Immunol. 13, 58–66 (2012).

    Article  CAS  Google Scholar 

  36. Halim, T. Y. et al. Retinoic-acid-receptor-related orphan nuclear receptor α is required for natural helper cell development and allergic inflammation. Immunity 37, 463–474 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Wong, S. H. et al. Transcription factor RORα is critical for nuocyte development. Nature Immunol. 13, 229–236 (2012).

    Article  CAS  Google Scholar 

  38. 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. Nature Immunol. 12, 1055–1062 (2011).

    Article  Google Scholar 

  39. Mjösberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).

    Article  PubMed  Google Scholar 

  40. 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 

  41. 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 

  42. Sanos, S. L., Vonarbourg, C., Mortha, A. & Diefenbach, A. Control of epithelial cell function by interleukin-22-producing RORγt+ innate lymphoid cells. Immunology 132, 453–465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Hoorweg, K. et al. Functional differences between human NKp44 and NKp44+ RORC+ innate lymphoid cells. Front. Immunol. 3, 72 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Cherrier, M. & Eberl, G. The development of LTi cells. Curr. Opin. Immunol. 24, 178–183 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Koyasu, S. & Moro, K. Role of innate lymphocytes in infection and inflammation. Front. Immunol. 3, 101 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Lee, J. S., Cella, M. & Colonna, M. AHR and the transcriptional regulation of type-17/22 ILC. Front. Immunol. 3, 10 (2012).

    PubMed  PubMed Central  Google Scholar 

  48. Walker, J. A. & McKenzie, A. Innate lymphoid cells in the airways. Eur. J. Immunol. 42, 1368–1374 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Sonnenberg, G. F. & Artis, D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank L. Lanier for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hergen Spits.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Spits, H., Artis, D., Colonna, M. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat Rev Immunol 13, 145–149 (2013). https://doi.org/10.1038/nri3365

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3365

This article is cited by

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