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:

The unusual suspects—innate lymphoid cells as novel therapeutic targets in IBD

Key Points

  • Innate lymphoid cells (ILCs) are a novel population of innate lymphocytes that are selectively enriched at mucosal sites

  • The ILC family comprises phenotypically and functionally distinct subsets that have been implicated in both maintenance and loss of mucosal homeostasis

  • ILCs are early producers of pathogenic cytokines in the intestine, such as interferon-γ and IL17, and have been implicated as important effector cells in preclinical models of inflammatory bowel disease (IBD)

  • Other ILC subsets produce cytokines involved in promoting intestinal epithelial homeostasis, such as IL-22, and might have protective roles in the gut

  • The number and composition of ILC subsets accumulating in the intestine of patients with IBD is dysregulated

  • Selective therapeutic targeting of ILCs might represent a novel treatment paradigm in IBD

Abstract

Innate lymphoid cells (ILCs) are a family of immune cells that selectively accumulate in mucosal tissues serving as sentinels at the vanguard of host protective immunity. However, they are also implicated as cellular mediators of immune-mediated diseases, most notably IBD. ILCs are subdivided into distinct lineages based on the expression of effector cytokines and master transcription factors that programme their differentiation and inflammatory behaviour. Strikingly, these subsets closely resemble CD4+ T-cell lineages, including T helper (TH)1, TH2 and TH17 cells that are similarly implicated in immune-mediated diseases. However, ILCs that promote the maintenance of intestinal epithelial cells, mostly through production of IL-22, also exist. ILCs rapidly respond to environmental cues, including cytokines, metabolic signals and luminal bacteria. They are potent and immediate producers of key cytokines linked to IBD pathogenesis, including TNF, IL-17, IL-22 and IFN-γ. Some subsets are implicated as mediators of chronic intestinal inflammation, whereas others might provide protective functions. They are present in the gut of patients with IBD and, intriguingly, closer scrutiny of IBD susceptibility loci shows that many of these genes are either expressed by, or are intimately linked to, ILC function. Looking forward, targeting ILCs could represent a new IBD treatment paradigm.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Human ILC subsets closely resemble T-cell lineages.
Figure 2: ILCs interact with other key mucosal cells in IBD.
Figure 3: Current and emerging therapeutic strategies in IBD and how they might affect ILC function.

Similar content being viewed by others

References

  1. Parronchi, P. et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am. J. Pathol. 150, 823–832 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Breese, E., Braegger, C. P., Corrigan, C. J., Walker-Smith, J. A. & MacDonald, T. T. Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology 78, 127–131 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Rovedatti, L. et al. Differential regulation of interleukin 17 and interferon γ production in inflammatory bowel disease. Gut 58, 1629–1636 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Heller, F. et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Biancheri, P. et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur. J. Immunol. 44, 370–385 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

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

    Article  CAS  Google Scholar 

  10. 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 

  11. 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 

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

    Article  CAS  PubMed  Google Scholar 

  13. Szabo, S. J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. 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 

  16. Reynders, A. et al. Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt lymphoid cells. EMBO J. 30, 2934–2947 (2011).

    Article  CAS  PubMed  PubMed Central  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).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. 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 

  20. Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Chinen, H. et al. Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells. Gastroenterology 133, 559–573 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Hall, L. J. et al. Natural killer cells protect mice from DSS-induced colitis by regulating neutrophil function via the NKG2A receptor. Mucosal Immunol. 6, 1016–1026 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Vonarbourg, C. et al. Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity 33, 736–751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Hazenberg, M. D. & Spits, H. Human innate lymphoid cells. Blood 124, 700–709 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. 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, E2559–2566 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Gökmen, K. R. et al. Genome wide regulatory analysis reveals that T-bet controls Th17 lineage differentiation through direct suppression of IRF4. J. Immunol. 191, 5925–5932 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Sawa, S. et al. RORgammat+ 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 

  35. Conti, H. R. et al. Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections. J. Exp. Med. 211, 2075–2084 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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  PubMed Central  Google Scholar 

  37. 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 

  38. 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 

  39. Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Garrett, W. S. et al. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 16, 208–219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Longman, R. S. et al. CX3CR1+ 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 

  42. Sanjabi, S., Zenewicz, L. A., Kamanaka, M. & Flavell, R. A. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr. Opin. Pharmacol. 9, 447–453 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Baert, F. et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology 138, 463–468 (2010).

    Article  PubMed  Google Scholar 

  46. Brakenhoff, L. K., van der Heijde, D. M., Hommes, D. W., Huizinga, T. W. & Fidder, H. H. The joint-gut axis in inflammatory bowel diseases. J. Crohns Colitis 4, 257–268 (2010).

    Article  PubMed  Google Scholar 

  47. De Vos, M., Mielants, H., Cuvelier, C., Elewaut, A. & Veys, E. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 110, 1696–1703 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cortes, A. et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730–738 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DeLay, M. L. et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum. 60, 2633–2643 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Azuz-Lieberman, N. et al. The involvement of NK cells in ankylosing spondylitis. Int. Immunol. 17, 837–845 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Bailey, J. R. et al. IL-13 promotes collagen accumulation in Crohn's disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS ONE 7, e52332 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hashguchi, M. et al. Peyer's patch innate lymphoid cells regulate commensal bacteria expansion. Immuno. Lett. 165, 1–9 (2015).

    Article  CAS  Google Scholar 

  55. Kamada, N. et al. TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease. Inflamm. Bowel Dis. 16, 568–575 (2010).

    Article  PubMed  Google Scholar 

  56. 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 

  57. von Burg, N. et al. Activated group 3 innate lymphoid cells promote T-cell-mediated immune responses. Proc. Natl Acad. Sci. USA 111, 12835–12840 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Norton, N.C. & Mathew, P. A. NKp44 and natural cytotoxicity receptors as damage-associated molecular pattern recognition receptors. Front. Immunol. 6, 31 (2015).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929–937 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bain, C. C. & Mowat, A. M. Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 260, 102–117 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bain, C. C. et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 6, 498–510 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Kamada, N. et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J. Clin. Invest. 118, 2269–2280 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Ogino, T. et al. Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn's disease. Gastroenterology 145, 1380–1391 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Mizuno, S. et al. Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease. Inflamm. Bowel Dis. 20, 1426–1434 (2014).

    Article  PubMed  Google Scholar 

  67. 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 

  68. 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 

  69. 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 

  70. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Xie, M. H. et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem. 275, 31335–31339 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Nagalakshmi, M L., Rascle, A., Zurawski, S., Menon, S. & de Waal Malefyt, R. Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int. Immunopharmacol. 4, 679–691 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. 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 

  78. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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. Mielke, L. A. et al. Retinoic acid expression associates with enhanced IL-22 production by gammadelta 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 

  83. Papier, K. et al. Childhood malnutrition and parasitic helminth interactions. Clin. Infect. Dis. 59, 234–243 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. 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 

  85. 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 

  86. Kiss, E. A. & Diefenbach, A. Role of the aryl hydrocarbon receptor in controlling maintenance and functional programs of RORgammat(+) innate lymphoid cells and intraepithelial lymphocytes. Front. Immunol. 3, 124 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hu, X. et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Aggarwal, S., Ghilardi, N., Xie, M. H., de Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Momozawa, Y. et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat. Genet. 43, 43–47 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Rivas, M. A. et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43, 1066–1073 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Biancheri, P., Powell, N., Monteleone, G., Lord, G. & MacDonald, T. T. The challenges of stratifying patients for trials in inflammatory bowel disease. Trends Immunol. 34, 564–571 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Kock, K. et al. Preclinical development of AMG 139, a human antibody specifically targetting IL-23. Br. J. Pharmacol. 172, 159–172 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sutton, C. E., Mielke, L. A. & Mills, K. H. IL-17-producing gammadelta T cells and innate lymphoid cells. Eur. J. Immunol. 42, 2221–2231 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N. Engl. J. Med. 367, 1519–1528 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Niederreiter, L., Adolph, T. E. & Kaser, A. Anti-IL-12/23 in Crohn's disease: bench and bedside. Curr. Drug Targets. 14, 1379–1384 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Satsangi, J. et al. Interleukin 1 in Crohn's disease. Clin. Exp. Immunol. 67, 594–605 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. McAlindon, M. E., Hawkey, C. J. & Mahida, Y. R. Expression of interleukin 1 beta and interleukin 1 beta converting enzyme by intestinal macrophages in health and inflammatory bowel disease. Gut 42, 214–219 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Reinecker, H. C. et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin. Exp. Immunol. 94, 174–181 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu, Z. et al. IL-15 is highly expressed in inflammatory bowel disease and regulates local T cell-dependent cytokine production. J. Immunol. 164, 3608–3615 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Monteleone, G., Fina, D., Caruso R. & Pallone, F. New mediators of immunity and inflammation in inflammatory bowel disease. Curr. Opin. Gastroenterol. 22, 361–364 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Ito, H. et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 126, 989–996 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 121, 3375–3383 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  107. Coccia, M. et al. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J. Exp. Med. 209, 1595–1609 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Nam, J. L. et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the update of the 2013 EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheumat. Dis. 73, 516–528 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396–2406 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Ilowite, N. T. et al. Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 66, 2570–2579 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chen, H. et al. Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3). Eur. J. Med. Chem. 82, 195–203 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bendell, J. C. et al. Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors. Cancer Chemother. Pharmacol. 74, 125–130 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Targan, S. R. et al. 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 [abstract Mo2083]. Gastroenterology 143, e26 (2012).

    Article  CAS  Google Scholar 

  114. Reinisch, W. et al. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm. Bowel Dis. 16, 233–242 (2010).

    Article  PubMed  Google Scholar 

  115. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Hanauer, S. B. et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359, 1541–1549 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  118. 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 

  119. Sandborn, W. J. et al. Natalizumab induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 353, 1912–1925 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 369, 711–721 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Rutgeerts, P. J. et al. A randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut 62, 1122–1130 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Watanabe, M. et al. AJM300, an oral α4 integrin antagonist, for active ulcerative colitis: a multicenter, randomized, double-blind, placebo-controlled phase 2a study [abstract 370]. Gastroenterology 146, S82 (2014).

    Article  Google Scholar 

  124. Vermeire, S. et al. The mucosal addressin cell adhesion molecule antibody PF-00547, 659 in ulcerative colitis: a randomised study. Gut 60, 1068–1075 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  126. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  127. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

Download references

Author information

Authors and Affiliations

Authors

Contributions

N.Powell, R.G. and N.Prescott contributed equally to researching data for the article, contributing to discussion of content and writing. All authors contributed equally to reviewing and editing the article before submission.

Corresponding author

Correspondence to Nick Powell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goldberg, R., Prescott, N., Lord, G. et al. The unusual suspects—innate lymphoid cells as novel therapeutic targets in IBD. Nat Rev Gastroenterol Hepatol 12, 271–283 (2015). https://doi.org/10.1038/nrgastro.2015.52

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2015.52

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing