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  • Review Article
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Innate lymphoid cells — how did we miss them?

Key Points

  • Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage with emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation.

  • The existence of different ILC populations that can rapidly secrete immunoregulatory cytokines suggests that these cells may have evolved to provide immunity to infections. Indeed, it is notable that ILC subsets seem to be particularly prevalent at mucosal surfaces, which are constantly exposed to infectious agents in the external environment.

  • The group 1 ILC lineage comprises ILCs such as natural killer (NK) cells that produce type 1 cytokines, notably interferon-γ and tumour necrosis factor. Other group 1 ILCs have been reported, mainly in vitro, and their physiological roles remain to be defined.

  • The group 2 ILC population comprises ILC2s, which express interleukin-5 (IL-5) and IL-13 and require GATA-binding protein 3 (GATA3) and retinoic acid receptor-related orphan receptor-α (RORα) for their development. They have crucial roles in protective type 2 immunity to helminth infection. Furthermore, although T helper 2 cells are a major source of type 2 cytokines during allergic asthma, ILC2s also contribute to disease pathology.

  • ILC3s were first defined as intestinal lymphoid cells that express the NK cell activating receptor NKp46, but otherwise bear little functional resemblance to conventional NK cells, and require RORγ for their development. They express IL-17A and IL-22.

  • Recent studies have also implicated ILC3s in the development of inflammatory bowel disease. Studies in Rag2−/− mice demonstrated that, in the early phase of Citrobacter rodentium infection, IL-22 is produced from an innate cell source.

  • Lymphoid tissue-inducer (LTi) cells are an ILC subset that appears to be closely related to ILC3s, but their exact relationship remains controversial. Together, LTi cells and ILC3s have been classified as group 3 ILCs.

Abstract

Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage that have emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the various ILC lineages that have been identified to date and summarize their functions in protective immunity to infection and their pathological roles in allergic and autoimmune diseases.

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Figure 1: ILC subsets, functions and disease associations.
Figure 2: A model for ILC development.
Figure 3: Schematic of the roles for ILCs in intestinal immune function.
Figure 4: Comparison of T helper cell and ILC subsets.

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References

  1. Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunol. 7 Jan 2013 (doi:10.1038/nri3365).

    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. Herberman, R. B., Nunn, M. E., Holden, H. T. & Lavrin, D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer. 16, 230–239 (1975).

    Article  CAS  PubMed  Google Scholar 

  4. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Di Santo, J. P. & Vosshenrich, C. A. Bone marrow versus thymic pathways of natural killer cell development. Immunol. Rev. 214, 35–46 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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). References 10–12 comprehensively characterize the group 2 ILCs (referred to as nuocytes, NHCs and I H 2 cells) that were first identified in references 7–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Bartemes, K. R. et al. IL-33-responsive lineageCD25+CD44hi lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J. Immunol. 188, 1505–1513 (2011).

    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. Kim, H. Y. et al. Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J. Allergy Clin. Immunol. 129, 216–227 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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 

  19. Wong, S. H. et al. Transcription factor RORα is critical for nuocyte development. Nature Immunol. 13, 229–236 (2012). References 18 and 19 illustrate the crucial role for the transcription factor RORα in the development of ILC2s.

    Article  CAS  Google Scholar 

  20. 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 

  21. Mjosberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012). References 20 and 21 characterize the role of the transcription factor GATA3 in ILC2 development in mice and humans.

    Article  PubMed  CAS  Google Scholar 

  22. Barlow, J. L. & McKenzie, A. N. Nuocytes: expanding the innate cell repertoire in type-2 immunity. J. Leukoc. Biol. 90, 867–874 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Mjosberg, 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). This paper is the first description of ILC2s in humans.

    Article  CAS  Google Scholar 

  24. 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 

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

    Article  CAS  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). References 24–26 are the first reports of intestinal lymphoid cells that express NKp46 but are distinct from NK cells and require the transcription factor ROR? for their development.

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. 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 

  29. 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 

  30. 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 

  31. Hughes, T. et al. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22. Blood 113, 4008–4010 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. Mebius, R. E., Streeter, P. R., Michie, S., Butcher, E. C. & Weissman, I. L. A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+ CD3 cells to colonize lymph nodes. Proc. Natl Acad. Sci. USA 93, 11019–11024 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoshida, H. et al. IL-7 receptor α+ CD3 cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11, 643–655 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. 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 

  37. 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 

  38. Withers, D. R. et al. Cutting edge: lymphoid tissue inducer cells maintain memory CD4 T cells within secondary lymphoid tissue. J. Immunol. 189, 2094–2098 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. 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 

  41. O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yoshida, H. et al. Expression of α4β7 integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J. Immunol. 167, 2511–2521 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Mebius, R. E. et al. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+CD4+CD3 cells, as well as macrophages. J. Immunol. 166, 6593–6601 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Yang, Q., Saenz, S. A., Zlotoff, D. A., Artis, D. & Bhandoola, A. Cutting edge: natural helper cells derive from lymphoid progenitors. J. Immunol. 187, 5505–5509 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Cherrier, M., Sawa, S. & Eberl, G. Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J. Exp. Med. 209, 729–740 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. 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 

  49. 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 

  50. 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 

  51. Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nature Immunol. 13, 144–151 (2012).

    Article  CAS  Google Scholar 

  53. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. 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 

  55. Hughes, T. et al. Interleukin-1β selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 32, 803–814 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010). This paper is the first description of ILCs in inflammatory bowel disease models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vonarbourg, C. & Diefenbach, A. Multifaceted roles of interleukin-7 signaling for the development and function of innate lymphoid cells. Semin. Immunol. 24, 165–174 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. 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 

  59. Bajoghli, B. et al. Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138, 186–197 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Alder, M. N. et al. Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310, 1970–1973 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Pancer, Z. et al. Variable lymphocyte receptors in hagfish. Proc. Natl Acad. Sci. USA 102, 9224–9229 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bajoghli, B. et al. A thymus candidate in lampreys. Nature 470, 90–94 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Saito, H. et al. Generation of intestinal T cells from progenitors residing in gut cryptopatches. Science 280, 275–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, T., Martin, S. A. & Secombes, C. J. Two interleukin-17C-like genes exist in rainbow trout Oncorhynchus mykiss that are differentially expressed and modulated. Dev. Comp. Immunol. 34, 491–500 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Tsutsui, S., Nakamura, O. & Watanabe, T. Lamprey (Lethenteron japonicum) IL-17 upregulated by LPS-stimulation in the skin cells. Immunogenetics 59, 873–882 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Ohtani, M., Hayashi, N., Hashimoto, K., Nakanishi, T. & Dijkstra, J. M. Comprehensive clarification of two paralogous interleukin 4/13 loci in teleost fish. Immunogenetics 60, 383–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Lane, P. J., Gaspal, F. M., McConnell, F. M., Withers, D. R. & Anderson, G. Lymphoid tissue inducer cells: pivotal cells in the evolution of CD4 immunity and tolerance? Front. Immunol. 3, 24 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Flores, M. V., Hall, C., Jury, A., Crosier, K. & Crosier, P. The zebrafish retinoid-related orphan receptor (ror) gene family. Gene Expr. Patterns 7, 535–543 (2007).

    Article  PubMed  CAS  Google Scholar 

  69. Fallon, P. G. et al. IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17, 7–17 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Finkelman, F. D. et al. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev. 201, 139–155 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Barner, M., Mohrs, M., Brombacher, F. & Kopf, M. Differences between IL-4R α-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 8, 669–672 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. McKenzie, G. J., Bancroft, A., Grencis, R. K. & McKenzie, A. N. A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr. Biol. 8, 339–342 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. 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  PubMed  PubMed Central  Google Scholar 

  74. Kang, Z. et al. Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Linc-Kit+ innate cell population. Immunity 36, 821–833 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  76. Zenewicz, L. A. & Flavell, R. A. Recent advances in IL-22 biology. Int. Immunol. 23, 159–163 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Vallance, B. A., Deng, W., Knodler, L. A. & Finlay, B. B. Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect. Immun. 70, 2070–2081 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. De Luca, A. et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol. 3, 361–373 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. Wolterink, R. G. et al. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur. J. Immunol. 42, 1106–1116 (2012).

    Article  CAS  Google Scholar 

  81. 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 

  82. Ikutani, M. et al. Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. J. Immunol. 188, 703–713 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Jackson, D. J., Sykes, A., Mallia, P. & Johnston, S. L. Asthma exacerbations: origin, effect, and prevention. J. Allergy Clin. Immunol. 128, 1165–1174 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Fuss, I. J. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Heller, F., Fuss, I. J., Nieuwenhuis, E. E., Blumberg, R. S. & Strober, W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17, 629–638 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. 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 

  88. Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208, 125–134 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Takayama, T. et al. Imbalance of NKp44+NKp46 and NKp44NKp46+ natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology 139, 882–892 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Fuss, I. J. et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261–1270 (1996).

    CAS  PubMed  Google Scholar 

  92. Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nature Immunol. 12, 320–326 (2011).

    Article  CAS  Google Scholar 

  93. Besnard, A. G. et al. Dual role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am. J. Respir. Crit. Care Med. 183, 1153–1163 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Schnyder, B., Lima, C. & Schnyder-Candrian, S. Interleukin-22 is a negative regulator of the allergic response. Cytokine 50, 220–227 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Taube, C. et al. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLoS ONE 6, e21799 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Takahashi, K. et al. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J. Allergy Clin. Immunol. 128, 1067–1076 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Barlow, J. L., Flynn, R. J., Ballantyne, S. J. & McKenzie, A. N. Reciprocal expression of IL-25 and IL-17A is important for allergic airways hyperreactivity. Clin. Exp. Allergy 41, 1447–1455 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. 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 

  99. Huntington, N. D., Vosshenrich, C. A. & Di Santo, J. P. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nature Rev. Immunol. 7, 703–714 (2007).

    Article  CAS  Google Scholar 

  100. Jackson, J. T. et al. Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages. EMBO J. 30, 2690–2704 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gascoyne, D. M. et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nature Immunol. 10, 1118–1124 (2009).

    Article  CAS  Google Scholar 

  102. Kamizono, S. et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206, 2977–2986 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  104. Samson, S. I. et al. GATA-3 promotes maturation, IFN-γ production, and liver-specific homing of NK cells. Immunity 19, 701–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Aliahmad, P., de la Torre, B. & Kaye, J. Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nature Immunol. 11, 945–952 (2010).

    Article  CAS  Google Scholar 

  107. Ohno, S. et al. Runx proteins are involved in regulation of CD122, Ly49 family and IFN-γ expression during NK cell differentiation. Int. Immunol. 20, 71–79 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Tachibana, M. et al. Runx1/Cbfβ2 complexes are required for lymphoid tissue inducer cell differentiation at two developmental stages. J. Immunol. 186, 1450–1457 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Sciumé, G. et al. Distinct requirements for T-bet in gut innate lymphoid cells. J. Exp. Med. 3 Dec 2012 (doi:10.1084/jem.20122097).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank S. Bell, C. Oliphant and S. Scanlon for critical appraisal of the manuscript. J.A.W. and A.N.J.M. are supported by the American Asthma Foundation.

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Correspondence to Andrew N. J. McKenzie.

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Glossary

Type 1 immune responses

Type 1 immune responses are characterized by the production of cytokines such as interferon-γ interleukin-2, tumour necrosis factor and lymphotoxin-α by various immune cells, including T helper 1 cells, neutrophils, macrophages and NK cells. Such responses protect against intracellular pathogens and are also implicated in several autoimmune diseases.

Type 2 immune responses

Type 2 immune responses are characterized by the secretion of cytokines such as interleukin-4 (IL-4), IL-5, IL-9 and IL-13 by various immune cells, including T helper 2 cells, eosinophils, basophils, mast cells and ILC2s. Such responses are required for controlling extracellular parasite infections, but they are also responsible for the immunopathology that develops in patients with allergy and asthma.

TH17 cells

A subset of CD4+ T helper cells that secrete predominantly the pro-inflammatory cytokine interleukin-17A and have been implicated in the pathogenesis of many chronic inflammatory disorders.

T follicular helper cells

(TFH cells). A subset of CD4+ helper T cells that interact with B cells within germinal centres to provide co-stimulatory signals and regulate the development of antigen-specific B cell immune responses.

OP9 cells

A bone marrow-derived stromal cell line used to support haematopoietic stem cells and common lymphoid progenitor cells during in vitro culture. The OP9–DL1 variation of this cell line ectopically expresses the Notch ligand Delta-like 1, which promotes the differentiation of T cells.

Common lymphoid progenitor

(CLP). CLPs are the earliest progenitors of the lymphoid cell lineages, which include B cells, T cells, NK cells and the newly described innate lymphoid cells. Bone marrow CLPs are defined by their expression of the IL-7 receptor, FMS-related tyrosine kinase 3 (FLT3) and KIT, and the absence of all conventional lineage markers.

Notch signalling

The Notch signalling pathway regulates cellular differentiation in various tissues and at various stages of development. During lymphopoiesis, signals through the Notch receptor modify gene expression patterns and have crucial roles in the development of T cells and the inhibition of B cell differentiation. In mammals, there are four Notch receptors, which bind to ligands of the Delta family (Delta-like 1, Delta-like 3 and Delta-like 4) and the jagged family (jagged 1 and jagged 2), which are typically expressed on stromal cells.

Aryl hydrocarbon receptor

(AHR). AHR is a cytosolic, ligand-dependent transcription factor that translocates to the nucleus following the binding of specific ligands, which include dietary and microbial metabolites. AHR participates in the differentiation of regulatory T cells, TH17 cells and intraepithelial intestinal γδ T cells, and it is required for the secretion of IL-22 by TH17 cells. More recently, AHR has been shown to have crucial roles in the development and function of LTi cells and ILC3s.

Forkhead box N1

(FOXN1). A winged-helix transcription factor that is thought to regulate keratin gene expression. Mutations in the Foxn1 gene result in a hairless ('nude') phenotype and athymia.

REG family of C-type lectins

Members of the REG3 subgroup of the C-type lectin family are antimicrobial peptides that interact with the peptidoglycans present on the surface of Gram-positive bacteria. They can be released into the intestinal lumen from multiple epithelial cell lineages.

Amphiregulin

A member of the epidermal growth factor family that drives the proliferation of epithelial cells and fibroblasts to promote tissue repair and remodelling in response to epithelial injury.

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Walker, J., Barlow, J. & McKenzie, A. Innate lymphoid cells — how did we miss them?. Nat Rev Immunol 13, 75–87 (2013). https://doi.org/10.1038/nri3349

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