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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

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

  2. 2

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

  3. 3

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

  4. 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).

  5. 5

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

  6. 6

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

  7. 7

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

  8. 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).

  9. 9

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

  10. 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).

  11. 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).

  12. 12

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

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 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).

  21. 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).

  22. 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).

  23. 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).

  24. 24

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

  25. 25

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

  26. 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).

  27. 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).

  28. 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).

  29. 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).

  30. 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).

  31. 31

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

  32. 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).

  33. 33

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

  34. 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).

  35. 35

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

  36. 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).

  37. 37

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

  38. 38

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

  39. 39

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

  40. 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).

  41. 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. 42

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

  43. 43

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

  44. 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).

  45. 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).

  46. 46

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

  47. 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).

  48. 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).

  49. 49

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

  50. 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).

  51. 51

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

  52. 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).

  53. 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).

  54. 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).

  55. 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).

  56. 56

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

  57. 57

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

  58. 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).

  59. 59

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

  60. 60

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

  61. 61

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

  62. 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. 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).

  64. 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).

  65. 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).

  66. 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).

  67. 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).

  68. 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).

  69. 69

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

  70. 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).

  71. 71

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

  72. 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).

  73. 73

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

  74. 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).

  75. 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).

  76. 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).

  77. 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).

  78. 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).

  79. 79

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

  80. 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).

  81. 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).

  82. 82

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

  83. 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).

  84. 84

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

  85. 85

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

  86. 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).

  87. 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).

  88. 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).

  89. 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).

  90. 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).

  91. 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).

  92. 92

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

  93. 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).

  94. 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).

  95. 95

    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).

  96. 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).

  97. 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).

  98. 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).

  99. 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).

  100. 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).

  101. 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).

  102. 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).

  103. 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).

  104. 104

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

  105. 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).

  106. 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).

  107. 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).

  108. 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).

  109. 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).

  110. 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).

  111. 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).

  112. 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).

  113. 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).

  114. 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).

  115. 115

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

  116. 116

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

  117. 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).

  118. 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).

  119. 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).

  120. 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).

  121. 121

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

  122. 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).

  123. 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).

  124. 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).

  125. 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).

  126. 126

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

  127. 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. 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).

  129. 129

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

  130. 130

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

  131. 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).

  132. 132

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

  133. 133

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

  134. 134

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

  135. 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).

  136. 136

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

  137. 137

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

  138. 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).

  139. 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).

  140. 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).

  141. 141

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

  142. 142

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

  143. 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).

  144. 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).

  145. 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).

  146. 146

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

  147. 147

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

  148. 148

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

  149. 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).

  150. 150

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

  151. 151

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

  152. 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. 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).

  154. 154

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

  155. 155

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

  156. 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).

  157. 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).

  158. 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).

  159. 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).

  160. 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).

  161. 161

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

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

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

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

Further reading