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.

  • Review Article
  • Published:

Innate lymphoid cells in the initiation, regulation and resolution of inflammation

Nature Medicine volume 21, pages 698–708 (2015)Cite this article

Subjects

Abstract

A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans and found to influence the induction, regulation and resolution of inflammation. ILCs have an important role in these processes in mouse models of infection, inflammation and tissue repair. Further, disease-association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be used to selectively modulate ILC responses and limit chronic inflammatory diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Development and heterogeneity of the ILC family.
Figure 2: ILCs promote acute inflammation and innate immunity to pathogens.
Figure 3: ILC2s and ILC3s promote the resolution of inflammation and tissue repair.
Figure 4: ILCs can promote chronic inflammation.
Figure 5: ILCs can prevent or limit chronic inflammation.

Similar content being viewed by others

References

  1. Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Walker, J.A., Barlow, J.L. & McKenzie, A.N. Innate lymphoid cells–how did we miss them? Nat. Rev. Immunol. 13, 75–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Sonnenberg, G.F., Mjösberg, J., Spits, H. & Artis, D. SnapShot: innate lymphoid cells. Immunity 39, 622 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. 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 

  8. Sonnenberg, G.F., Fouser, L.A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Aujla, S.J. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat. Med. 14, 275–281 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ouyang, W., Kolls, J.K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Harrington, L.E., Mangan, P.R. & Weaver, C.T. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr. Opin. Immunol. 18, 349–356 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Ahern, P.P., Izcue, A., Maloy, K.J. & Powrie, F. The interleukin-23 axis in intestinal inflammation. Immunol. Rev. 226, 147–159 (2008).

    Article  PubMed  Google Scholar 

  13. 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 

  14. Saenz, S.A., Taylor, B.C. & Artis, D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol. Rev. 226, 172–190 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liew, F.Y., Pitman, N.I. & McInnes, I.B. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat. Rev. Immunol. 10, 103–110 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Liu, Y.J. et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193–219 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. 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 

  19. Pross, H.F. & Jondal, M. Cytotoxic lymphocytes from normal donors. A functional marker of human non-T lymphocytes. Clin. Exp. Immunol. 21, 226–235 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. 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 

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

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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  CAS  PubMed  Google Scholar 

  33. 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 

  34. 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 

  35. Constantinides, M.G., McDonald, B.D., Verhoef, P.A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. 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 

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

    Article  CAS  PubMed  Google Scholar 

  39. Xu, W. et al. NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep. 10, 2043–2054 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Geiger, T.L. et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J. Exp. Med. 211, 1723–1731 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yu, X. et al. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. elife http://dx.doi.org/10.7554/eLife.0440 (2014).

  42. Seillet, C. et al. Nfil3 is required for the development of all innate lymphoid cell subsets. J. Exp. Med. 211, 1733–1740 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kobayashi, T. et al. NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis. J. Immunol. 192, 1918–1927 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Seehus, C.R. et al. The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nat. Immunol. 16, 599–608 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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. Nat. Immunol. 11, 945–952 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang, Q. et al. T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38, 694–704 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mielke, L.A. et al. TCF-1 controls ILC2 and NKp46+RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation. J. Immunol. 191, 4383–4391 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Yagi, R. et al. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40, 378–388 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Serafini, N. et al. Gata3 drives development of RORγt+ group 3 innate lymphoid cells. J. Exp. Med. 211, 199–208 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Montaldo, E. et al. Human RORγt+CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity 41, 988–1000 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. 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  CAS  PubMed  Google Scholar 

  55. Klein Wolterink, R.G. et al. Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL-13+ type 2 innate lymphoid cells. Proc. Natl. Acad. Sci. USA 110, 10240–10245 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Furusawa, J. et al. Critical role of p38 and GATA3 in natural helper cell function. J. Immunol. 191, 1818–1826 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Spooner, C.J. et al. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat. Immunol. 14, 1229–1236 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Walker, J.A. et al. Bcl11b is essential for group 2 innate lymphoid cell development. J. Exp. Med. (in the press, 2015).

  62. Yu, Y. et al. The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J. Exp. Med. (in the press, 2015).

  63. Kim, B.S. et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl. Med. 5, 70ra116 (2013).

    Article  CAS  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. 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 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  70. 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).

    Article  CAS  Google Scholar 

  71. 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 

  72. 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 

  73. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Mackley, E.C. et al. CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nat. Commun. 6, 5862 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. 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 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. Sun, J.C. & Lanier, L.L. NK cell development, homeostasis and function: parallels with CD8+ T cells. Nat. Rev. Immunol. 11, 645–657 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Maizels, R.M., Hewitson, J.P. & Smith, K.A. Susceptibility and immunity to helminth parasites. Curr. Opin. Immunol. 24, 459–466 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Artis, D. et al. RELMβ/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc. Natl. Acad. Sci. USA 101, 13596–13600 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Pham, T.A. et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 16, 504–516 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Pickard, J.M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638–641 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. Sonnenberg, G.F. et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med. 207, 1293–1305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Deshmukh, H.S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Turner, J.E. et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Scandella, E. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Matsumoto, A. et al. IL-22-producing RORgammat-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis. PLoS ONE 8, e62853 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kumar, P., Thakar, M.S., Ouyang, W. & Malarkannan, S. IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol. 6, 69–82 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  96. Ciccia, F. et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 64, 1869–1878 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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 

  99. Mielke, L.A. et al. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210, 1117–1124 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Munneke, J.M. et al. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 124, 812–821 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Zaph, C. et al. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J. Exp. Med. 205, 2191–2198 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Longman, R.S. et al. CX(3)CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J. Exp. Med. 211, 1571–1583 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Manta, C. et al. CX(3)CR1+ macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium. Mucosal Immunol. 6, 177–188 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Aychek, T. et al. IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium–induced colon immunopathology. Nat. Commun. 6, 6525 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. Franchi, L. et al. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat. Immunol. 13, 449–456 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Seo, S.U. et al. Distinct commensals induce interleukin-1β via NLRP3 inflammasome in inflammatory monocytes to promote intestinal inflammation in response to injury. Immunity 42, 744–755 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bartemes, K.R., Kephart, G.M., Fox, S.J. & Kita, H. Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J. Allergy Clin. Immunol. 134, 671–678 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hams, E. et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 111, 367–372 (2014).

    Article  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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 

  113. Bartemes, K.R. et al. IL-33-responsive lineage+CD25+CD44hi lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J. Immunol. 188, 1503–1513 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Kabata, H. et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat. Commun. 4, 2675 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  117. 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).

    Article  CAS  PubMed  Google Scholar 

  118. Barnig, C. et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci. Transl. Med. 5, 74ra126 (2013).

    Article  CAS  Google Scholar 

  119. Halim, T.Y. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mirchandani, A.S. et al. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. J. Immunol. 192, 2442–2448 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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 

  127. Powell, N. et al. Interleukin-6 increases production of cytokines by colonic innate lymphoid cells in mice and patients with chronic intestinal inflammation. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2015.04.017 (2015).

  128. Ermann, J., Staton, T., Glickman, J.N., de Waal Malefyt, R. & Glimcher, L.H. Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet−/−Rag2−/− (TRUC) mice. Proc. Natl. Acad. Sci. USA 111, E2559–E2566 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Muñoz, M. et al. Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42, 321–331 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Klatt, N.R. et al. Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection. Mucosal Immunol. 5, 646–657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Gray, E.E., Friend, S., Suzuki, K., Phan, T.G. & Cyster, J.G. Subcapsular sinus macrophage fragmentation and CD169+ bleb acquisition by closely associated IL-17-committed innate-like lymphocytes. PLoS ONE 7, e38258 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kim, C.J. et al. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol. 5, 670–680 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Li, H. et al. Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. PLoS Pathog. 10, e1004551 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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 

  143. Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Brenchley, J.M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006).

    Article  CAS  PubMed  Google Scholar 

  145. Guo, X. et al. Innate lymphoid cells control early colonization resistance against intestinal pathogens through ID2-dependent regulation of the microbiota. Immunity 42, 731–743 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hepworth, M.R. & Sonnenberg, G.F. Regulation of the adaptive immune system by innate lymphoid cells. Curr. Opin. Immunol. 27, 75–82 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  149. 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).

    Article  CAS  PubMed  Google Scholar 

  150. Hepworth, M.R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Goto, Y. et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40, 594–607 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hepworth, M.R. et al. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science (in the press, 2015).

  153. Perry, J.S. et al. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci. Transl. Med. 4, ra106 (2012).

    Article  CAS  Google Scholar 

  154. Papp, K.A. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N. Engl. J. Med. 366, 1181–1189 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Genovese, M.C. et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 62, 929–939 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Bowman, E.P., Chackerian, A.A. & Cua, D.J. Rationale and safety of anti-interleukin-23 and anti-interleukin-17A therapy. Curr. Opin. Infect. Dis. 19, 245–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  158. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Targan, S.R. et al. Mo2083 A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn's disease. Gastroenterology 143, e26 (2014).

    Article  CAS  Google Scholar 

  160. Kaser, A. Not all monoclonals are created equal: lessons from failed drug trials in Crohn's disease. Best Pract. Res. Clin. Gastroenterol. 28, 437–449 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. Colombel, J.F., Sendid, B., Jouault, T. & Poulain, D. Secukinumab failure in Crohn's disease: the yeast connection? Gut 62, 800–801 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research in the Sonnenberg laboratory is supported by the US National Institutes of Health (NIH) (DP5OD012116), the National Institute of Allergy and Infectious Disease Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity and the Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the US National Center for Research Resources). Research in the Artis laboratory is supported by the NIH (AI061570, AI074878, AI095466, AI095608, AI102942, AI097333 and AI106697), the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award and the Crohn's and Colitis Foundation of America.

Author information

Authors and Affiliations

  1. Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA

    Gregory F Sonnenberg & David Artis

  2. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA

    Gregory F Sonnenberg & David Artis

  3. The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, New York, New York, USA

    Gregory F Sonnenberg & David Artis

Authors
  1. Gregory F Sonnenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Artis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregory F Sonnenberg.

Ethics declarations

Competing interests

David Artis is a scientific advisor for Bio-Techne and Second Genome, although these programs are not referred to herein.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sonnenberg, G., Artis, D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 21, 698–708 (2015). https://doi.org/10.1038/nm.3892

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3892

Search

Advanced 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