Skip to main content

Advertisement

Log in

Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis

  • Review Article
  • Published:

From Nature Immunology

View current issue Submit your manuscript

Abstract

Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Canada)

Instant access to the full article PDF.

Figure 1: The distribution of ILCs at the mucosa of the intestine.
Figure 2: Integration of ILC2s in the type 2 immune response.
Figure 3: ILC3 responses at epithelial barriers.

Similar content being viewed by others

References

  1. Spits, H., Bernink, J.H. & Lanier, L. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat. Immunol. 17, –http://dx.doi.org/10.1038/ni.3482 (2016).

  2. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. Diefenbach, A., Colonna, M. & Koyasu, S. Development, differentiation, and diversity of innate lymphoid cells. Immunity 41, 354–365 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Eberl, G., Colonna, M., Di Santo, J.P. & McKenzie, A.N. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science 348, aaa6566 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. Spits, H. et al. Innate lymphoid cells--a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Klose, C.S. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    PubMed  Google Scholar 

  9. 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 

  10. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Klose, C.S. et al. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).

    CAS  PubMed  Google Scholar 

  14. 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 

  15. Eberl, G. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Mebius, R.E., Rennert, P. & Weissman, I.L. Developing lymph nodes collect CD4+CD3LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).

    CAS  PubMed  Google Scholar 

  17. Gladiator, A., Wangler, N., Trautwein-Weidner, K. & LeibundGut-Landmann, S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521–525 (2013).

    CAS  PubMed  Google Scholar 

  18. Rankin, L.C. et al. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nat. Immunol. 14, 389–395 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    CAS  PubMed  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bernink, J.H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).

    CAS  PubMed  Google Scholar 

  22. Ishizuka, I.E. et al. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat. Immunol. 17, 269–276 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lucas, M., Schachterle, W., Oberle, K., Aichele, P. & Diefenbach, A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Satoh-Takayama, N. et al. The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells. Immunity 41, 776–788 (2014).

    CAS  PubMed  Google Scholar 

  25. Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gasteiger, G., Fan, X., Dikiy, S., Lee, S.Y. & Rudensky, A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Moro, K. et al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat. Immunol. 17, 76–86 (2016).

    CAS  PubMed  Google Scholar 

  28. Bando, J.K., Liang, H.E. & Locksley, R.M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat. Immunol. 16, 153–160 (2015).

    CAS  PubMed  Google Scholar 

  29. Kim, M.H., Taparowsky, E.J. & Kim, C.H. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity 43, 107–119 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hepworth, M.R. et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4 T cells. Science 348, 1031–1035 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Fan, X. & Rudensky, A.Y. Hallmarks of tissue-resident lymphocytes. Cell 164, 1198–1211 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bando, J.K. & Colonna, M. et al. Innate lymphoid cell function in the context of adaptive immunity. Nat. Immunol. 17, http://dx.doi.org/10.1038/ni.3484 (2016).

  33. Robinette, M.L. et al. Immunological Genome Consortium. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, B.S. et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl. Med. 5, 170ra16 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat. Immunol. 14, 564–573 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Motomura, Y. et al. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40, 758–771 (2014).

    CAS  PubMed  Google Scholar 

  37. Wojno, E.D. et al. The prostaglandin D receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung. Mucosal Immunol. 8, 1313–1323 (2015).

    PubMed  Google Scholar 

  38. Doherty, T.A. et al. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J. Allergy Clin. Immunol. 132, 205–213 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Meylan, F. et al. The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. Mucosal Immunol. 7, 958–968 (2014).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Longman, R.S. et al. CX3 CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J. Exp. Med. 211, 1571–1583 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hernández, P.P. et al. Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. Nat. Immunol. 16, 698–707 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. Kim, H.Y. et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat. Med. 20, 54–61 (2014).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    CAS  PubMed  Google Scholar 

  48. Saenz, S.A. et al. IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells. J. Exp. Med. 210, 1823–1837 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang, Y. et al. IL-25-responsive, lineage-negative KLRG1hi cells are multipotential 'inflammatory' type 2 innate lymphoid cells. Nat. Immunol. 16, 161–169 (2015).

    CAS  PubMed  Google Scholar 

  50. Diefenbach, A. & Raulet, D.H. Innate immune recognition by stimulatory immunoreceptors. Curr. Opin. Immunol. 15, 37–44 (2003).

    CAS  PubMed  Google Scholar 

  51. Guerra, N. et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28, 571–580 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gazit, R. et al. Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat. Immunol. 7, 517–523 (2006).

    CAS  PubMed  Google Scholar 

  53. Glatzer, T. et al. RORγt+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity 38, 1223–1235 (2013).

    CAS  PubMed  Google Scholar 

  54. Satoh-Takayama, N. et al. The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium. J. Immunol. 183, 6579–6587 (2009).

    CAS  PubMed  Google Scholar 

  55. Maazi, H. et al. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 42, 538–551 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Paclik, D., Stehle, C., Lahmann, A., Hutloff, A. & Romagnani, C. ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice. Eur. J. Immunol. 45, 2766–2772 (2015).

    CAS  PubMed  Google Scholar 

  57. Salimi, M. et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210, 2939–2950 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Gründemann, C. et al. The NK receptor KLRG1 is dispensable for virus-induced NK and CD8+ T-cell differentiation and function in vivo. Eur. J. Immunol. 40, 1303–1314 (2010).

    PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Salimi, M. et al. Group 2 innate lymphoid cells express functional NKp30 receptor inducing type 2 cytokine production. J. Immunol. 196, 45–54 (2016).

    CAS  PubMed  Google Scholar 

  61. van de Pavert, S.A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Spencer, S.P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Veldhoen, M. & Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat. Rev. Immunol. 12, 696–708 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  65. 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. Nat. Immunol. 13, 144–151 (2012).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Song, C. et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869–1882 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Nussbaum, J.C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zenewicz, L.A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    PubMed  PubMed Central  Google Scholar 

  72. 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).

    CAS  PubMed  Google Scholar 

  73. Zhang, B. et al. Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 346, 861–865 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Brestoff, J.R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

    CAS  PubMed  Google Scholar 

  76. Kruglov, A.A. et al. Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science 342, 1243–1246 (2013).

    CAS  PubMed  Google Scholar 

  77. Goto, Y. et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345, 1254009 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. van de Pavert, S.A. & Mebius, R.E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).

    CAS  PubMed  Google Scholar 

  79. Tumanov, A.V. et al. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10, 44–53 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ota, N. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat. Immunol. 12, 941–948 (2011).

    CAS  PubMed  Google Scholar 

  81. Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008).

    CAS  PubMed  Google Scholar 

  82. Magri, G. et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat. Immunol. 15, 354–364 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. von Burg, N., Turchinovich, G. & Finke, D. Maintenance of Immune Homeostasis through ILC/T Cell Interactions. Front. Immunol. 6, 416 (2015).

    PubMed  PubMed Central  Google Scholar 

  84. Oliphant, C.J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Duerr, C.U. et al. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat. Immunol. 17, 65–75 (2016).

    CAS  PubMed  Google Scholar 

  86. Molofsky, A.B. et al. Interleukin-33 and Interferon-γ counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity 43, 161–174 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  88. Giacomin, P.R. et al. Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity. J. Exp. Med. 212, 1513–1528 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gasteiger, G., Hemmers, S., Bos, P.D., Sun, J.C. & Rudensky, A.Y. IL-2-dependent adaptive control of NK cell homeostasis. J. Exp. Med. 210, 1179–1187 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Krishnamoorthy, N. et al. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J. Immunol. 194, 863–867 (2015).

    CAS  PubMed  Google Scholar 

  91. Barnig, C. & Levy, B.D. Innate immunity is a key factor for the resolution of inflammation in asthma. Eur. Resp. Rev. 24, 141–153 (2015).

    Google Scholar 

  92. 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  PubMed  PubMed Central  Google Scholar 

  93. 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).

    CAS  PubMed  Google Scholar 

  94. Zaiss, D.M. et al. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314, 1746 (2006).

    CAS  PubMed  Google Scholar 

  95. Yasuda, K. et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc. Natl. Acad. Sci. USA 109, 3451–3456 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. von Moltke, J., Ji, M., Liang, H.E. & Locksley, R.M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225 (2016).

    CAS  PubMed  Google Scholar 

  97. Howitt, M.R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).

    CAS  PubMed  Google Scholar 

  99. Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).

    CAS  PubMed  Google Scholar 

  100. Satpathy, A.T. et al. Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat. Immunol. 14, 937–948 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rankin, L.C. et al. Complementarity and redundancy of IL-22-producing innate lymphoid cells. Nat. Immunol. 17, 179–186 (2016).

    CAS  PubMed  Google Scholar 

  102. Basu, R. et al. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Karo, J.M., Schatz, D.G. & Sun, J.C. The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell 159, 94–107 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Okada, S. et al. Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349, 606–613 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Sparber, F. & LeibundGut-Landmann, S. Interleukin 17-mediated host defense against Candida albicans. Pathogens 4, 606–619 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Nausch, N. et al. Group 2 innate lymphoid cell proportions are diminished in young helminth infected children and restored by curative anti-helminthic treatment. PLoS Negl. Trop. Dis. 9, e0003627 (2015).

    PubMed  PubMed Central  Google Scholar 

  107. Boyd, A., Ribeiro, J.M. & Nutman, T.B. Human CD117 (cKit)+ innate lymphoid cells have a discrete transcriptional profile at homeostasis and are expanded during filarial infection. PLoS One 9, e108649 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. Li, J., Zhang, Y. & Zhang, L. Discovering susceptibility genes for allergic rhinitis and allergy using a genome-wide association study strategy. Curr. Opin. Allergy Clin. Immunol. 15, 33–40 (2015).

    CAS  PubMed  Google Scholar 

  109. Imai, Y. et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc. Natl. Acad. Sci. USA 110, 13921–13926 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kim, B.S. et al. Basophils promote innate lymphoid cell responses in inflamed skin. J. Immunol. 193, 3717–3725 (2014).

    CAS  PubMed  Google Scholar 

  111. 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  PubMed  PubMed Central  Google Scholar 

  112. 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).

    PubMed  Google Scholar 

  113. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  116. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Teunissen, M.B. et al. Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients. J. Invest. Dermatol. 134, 2351–2360 (2014).

    CAS  PubMed  Google Scholar 

  119. Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014).

    CAS  PubMed  Google Scholar 

  120. Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252–2256 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Cording, S., Medvedovic, J., Aychek, T. & Eberl, G. ILCs in defense, immunopathology and immunotherapy. Nat. Immunol. 17, http://dx.doi.org/10.1038/ni.3448 (2016).

  122. Monticelli, L.A. et al. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc. Natl. Acad. Sci. USA 112, 10762–10767 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Rak, G.D. et al. IL-33-Dependent group 2 innate lymphoid cells promote cutaneous wound healing. J. Invest. Dermatol. 136, 487–496 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  PubMed  Google Scholar 

  126. Dudakov, J.A. et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336, 91–95 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Lindemans, C.A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Aparicio-Domingo, P. et al. Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J. Exp. Med. 212, 1783–1791 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Duffin, R. et al. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science 351, 1333–1338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Jovanovic, I.P. et al. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int. J. Cancer 134, 1669–1682 (2014).

    CAS  PubMed  Google Scholar 

  133. 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).

    CAS  PubMed  Google Scholar 

  134. Dadi, S. et al. Cancer Immunosurveillance by tissue-resident innate lymphoid cells and innate-like t cells. Cell 164, 365–377 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Eisenring, M., vom Berg, J., Kristiansen, G., Saller, E. & Becher, B. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat. Immunol. 11, 1030–1038 (2010).

    CAS  PubMed  Google Scholar 

  136. Carrega, P. et al. NCR+ ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat. Commun. 6, 8280 (2015).

    CAS  PubMed  Google Scholar 

  137. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Brestoff, J.R. & Artis, D. Immune regulation of metabolic homeostasis in health and disease. Cell 161, 146–160 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Molofsky, A.B. et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Hams, E., Locksley, R.M., McKenzie, A.N. & Fallon, P.G. Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J. Immunol. 191, 5349–5353 (2013).

    CAS  PubMed  Google Scholar 

  144. Lee, M.W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).

    CAS  PubMed  Google Scholar 

  145. Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014).

    CAS  PubMed  Google Scholar 

  146. Halim, T.Y. Group 2 innate lymphoid cells in disease. Int. Immunol. 28, 13–22 (2016).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Mahlakoiv, L.C. Rankin and A.-L. Flamar for critical reading of the manuscript. Supported by the US National Institutes of Health (AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942, and AI097333 for the Artis laboratory), the Burroughs Wellcome Fund (Artis laboratory) and the Crohn's & Colitis Foundation of America (Artis laboratory).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David Artis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klose, C., Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol 17, 765–774 (2016). https://doi.org/10.1038/ni.3489

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.3489

  • Springer Nature America, Inc.

This article is cited by

Navigation