Review Article | Published:

Targeting immune cell circuits and trafficking in inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are characterized by uncontrolled activation of intestinal immune cells in a genetically susceptible host. Due to the progressive and destructive nature of the inflammatory process in IBD, complications such as fibrosis, stenosis or cancer are frequently observed, which highlights the need for effective anti-inflammatory therapy. Studies have identified altered trafficking of immune cells and pathogenic immune cell circuits as crucial drivers of mucosal inflammation and tissue destruction in IBD. A defective gut barrier and microbial dysbiosis induce such accumulation and local activation of immune cells, which results in a pro-inflammatory cytokine loop that overrides anti-inflammatory signals and causes chronic intestinal inflammation. This Review discusses pathogenic cytokine responses of immune cells as well as immune cell trafficking as a rational basis for new translational therapies in IBD.

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References

  1. 1.

    Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2018).

  2. 2.

    Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007).

  3. 3.

    Yilmaz, B. et al. Microbial network disturbances in relapsing refractory Crohn’s disease. Nat. Med. 25, 323–336 (2019).

  4. 4.

    Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387, 156–167 (2016).

  5. 5.

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

  6. 6.

    Parkes, M. The genetics universe of Crohn’s disease and ulcerative colitis. Dig. Dis. 30, 78–81 (2012).

  7. 7.

    Kiesslich, R. et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut 61, 1146–1153 (2012).

  8. 8.

    Chang, S. Y. et al. Circulatory antigen processing by mucosal dendritic cells controls CD8+ T cell activation. Immunity 38, 153–165 (2013).

  9. 9.

    Podolsky, D. K. et al. Attenuation of colitis in the cotton-top tamarin by anti-α4 integrin monoclonal antibody. J. Clin. Invest. 92, 372–380 (1993).

  10. 10.

    Sugiura, T. et al. Oral treatment with a novel small molecule α4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J. Crohn’s Colitis 7, e533–e542 (2013).

  11. 11.

    Ghosh, S. et al. Natalizumab for active Crohn’s disease. N. Engl. J. Med. 348, 24–32 (2003).

  12. 12.

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

  13. 13.

    Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N. Engl. J. Med. 353, 362–368 (2005).

  14. 14.

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

  15. 15.

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

  16. 16.

    Sandborn, W. J. et al. Efficacy and safety of abrilumab in a randomized, placebo-controlled trial for moderate-to-severe ulcerative colitis. Gastroenterology 156, 946–957.e918 (2019).

  17. 17.

    Wyant, T., Yang, L. & Fedyk, E. In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes. MAbs 5, 842–850 (2013).

  18. 18.

    Zundler, S. et al. Three-dimensional cross-sectional light-sheet microscopy imaging of the inflamed mouse gut. Gastroenterology 153, 898–900 (2017).

  19. 19.

    Uzzan, M. et al. Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals. Sci. Transl. Med. 10, eaau4711 (2018).

  20. 20.

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

  21. 21.

    Schleier, L. et al. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut https://doi.org/10.1136/gutjnl-2018-316772 (2019).

  22. 22.

    Vermeire, S. et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 390, 135–144 (2017).

  23. 23.

    Sandborn, W. J. et al. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn’s disease: report of the OPERA study. Gut 67, 1824–1835 (2018).

  24. 24.

    van Deventer, S. J., Tami, J. A. & Wedel, M. K. A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis. Gut 53, 1646–1651 (2004).

  25. 25.

    Greuter, T., Biedermann, L., Rogler, G., Sauter, B. & Seibold, F. Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: A case series. United European Gastroenterol. J. 4, 97–104 (2016).

  26. 26.

    Feagan, B. G. et al. Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as induction therapy in active Crohn’s disease. Aliment. Pharmacol. Ther. 42, 1170–1181 (2015).

  27. 27.

    Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384, 309–318 (2014).

  28. 28.

    Agace, W. W., Higgins, J. M., Sadasivan, B., Brenner, M. B. & Parker, C. M. T-lymphocyte-epithelial-cell interactions: integrin αE(CD103)β7, LEEP-CAM and chemokines. Curr. Opin. Cell Biol. 12, 563–568 (2000).

  29. 29.

    Lamb, C. A. et al. αEβ7 integrin identifies subsets of pro-inflammatory colonic CD4+ T lymphocytes in ulcerative colitis. J. Crohn’s Colitis 11, 610–620 (2017).

  30. 30.

    Zundler, S. et al. Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut 11, 1936–1948 (2016).

  31. 31.

    Zundler, S. et al. Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation. Nat. Immunol. 20, 288–300 (2019).

  32. 32.

    Bishu, S. et al. CD4+ tissue-resident memory T cells expand and are a major source of mucosal tumour necrosis factor α in active Crohn’s disease. J. Crohn’s Colitis https://doi.org/10.1093/ecco-jcc/jjz010 (2019).

  33. 33.

    Sandborn, W. J. et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N. Engl. J. Med. 374, 1754–1762 (2016).

  34. 34.

    West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).

  35. 35.

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

  36. 36.

    Neurath, M. F., Fuss, I., Kelsall, B. L., Stüber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–1290 (1995).

  37. 37.

    Gerlach, K. et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol. 15, 676–686 (2014).

  38. 38.

    Monteleone, G. et al. Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology 112, 1169–1178 (1997).

  39. 39.

    Kotlarz, D. et al. Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat. Genet. 50, 344–348 (2018).

  40. 40.

    Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

  41. 41.

    Kotlarz, D. et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143, 347–355 (2012).

  42. 42.

    Caudy, A. A., Reddy, S. T., Chatila, T., Atkinson, J. P. & Verbsky, J. W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119, 482–487 (2007).

  43. 43.

    Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

  44. 44.

    Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

  45. 45.

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

  46. 46.

    Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).

  47. 47.

    Colombel, J. F. et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N. Engl. J. Med. 362, 1383–1395 (2010).

  48. 48.

    Panaccione, R. et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 146, 392–400.e3 (2014).

  49. 49.

    Feagan, B. G. et al. Ustekinumab as induction and maintenance therapy for crohn’s disease. N. Engl. J. Med. 375, 1946–1960 (2016).

  50. 50.

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

  51. 51.

    Danese, S. et al. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 64, 243–249 (2015).

  52. 52.

    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).

  53. 53.

    Reinisch, W. et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease. Gut 55, 1138–1144 (2006).

  54. 54.

    Danese, S. et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut 68, 40–48 (2019).

  55. 55.

    Wirtz, S., Becker, C., Blumberg, R., Galle, P. R. & Neurath, M. F. Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA. J. Immunol. 168, 411–420 (2002).

  56. 56.

    Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50, 778–795 (2019).

  57. 57.

    Casini-Raggi, V. et al. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J. Immunol. 154, 2434–2440 (1995).

  58. 58.

    Shouval, D. S. et al. Interleukin 1β mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency. Gastroenterology 151, 1100–1104 (2016).

  59. 59.

    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).

  60. 60.

    Dmitrieva-Posocco, O. et al. Cell-type-specific responses to interleukin-1 control microbial invasion and tumor-elicited inflammation in colorectal cancer. Immunity 50, 166–180.e167 (2019).

  61. 61.

    Cominelli, F. et al. Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J. Clin. Invest. 86, 972–980 (1990).

  62. 62.

    Bauer, C. et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59, 1192–1199 (2010).

  63. 63.

    Castro-Dopico, T. et al. Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis. Immunity 50, 1099–1114.e10 (2019).

  64. 64.

    Siegmund, B., Lehr, H. A., Fantuzzi, G. & Dinarello, C. A. IL-1β-converting enzyme (caspase-1) in intestinal inflammation. Proc. Natl Acad. Sci. USA 98, 13249–13254 (2001).

  65. 65.

    Neudecker, V. et al. Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J. Exp. Med. 214, 1737–1752 (2017).

  66. 66.

    Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

  67. 67.

    Ten Hove, T. et al. Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-α production in mice. Gastroenterology 121, 1372–1379 (2001).

  68. 68.

    Kanai, T. et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterology 121, 875–888 (2001).

  69. 69.

    Pizarro, T. T. et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells. J. Immunol. 162, 6829–6835 (1999).

  70. 70.

    Pastorelli, L. et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc. Natl Acad. Sci. USA 107, 8017–8022 (2010).

  71. 71.

    Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl Acad. Sci. USA 107, 18581–18586 (2010).

  72. 72.

    He, Z. et al. Mast cells are essential intermediaries in regulating IL-33/ST2 signaling for an immune network favorable to mucosal healing in experimentally inflamed colons. Cell Death Dis. 9, 1173 (2018).

  73. 73.

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

  74. 74.

    Russell, S. E. et al. IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation. Mucosal Immunol. 9, 1193–1204 (2016).

  75. 75.

    Scheibe, K. et al. IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo. Gut 66, 823–838 (2017).

  76. 76.

    Medina-Contreras, O. et al. Cutting edge: IL-36 receptor promotes resolution of intestinal damage. J. Immunol. 196, 34–38 (2016).

  77. 77.

    Ngo, V. L. et al. A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage. Proc. Natl Acad. Sci. USA 115, E5076–E5085 (2018).

  78. 78.

    Scheibe, K. et al. Inhibiting Interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology 156, 1082–1097.e1011 (2019).

  79. 79.

    Imaeda, H. et al. Epithelial expression of interleukin-37b in inflammatory bowel disease. Clin. Exp. Immunol. 172, 410–416 (2013).

  80. 80.

    McNamee, E. N. et al. Interleukin 37 expression protects mice from colitis. Proc. Natl Acad. Sci. USA 108, 16711–16716 (2011).

  81. 81.

    Wang, W. Q. et al. IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice. Acta Pharmacol. Sin. 36, 1377–1387 (2015).

  82. 82.

    Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat. Med. 6, 583–588 (2000).

  83. 83.

    Atreya, R. & Neurath, M. F. Signaling molecules: the pathogenic role of the IL-6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer. Curr. Drug Targets 9, 369–374 (2008).

  84. 84.

    Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

  85. 85.

    Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21, 491–501 (2004).

  86. 86.

    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). discussion 947.

  87. 87.

    Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).

  88. 88.

    Atreya, R. et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages. Gastroenterology 141, 2026–2038 (2011).

  89. 89.

    Atreya, R. et al. In vivo molecular imaging using fluorescent anti-TNF antibodies predicts response to biological therapy in Crohn’s disease. Nat. Med. 52, 313–318 (2014).

  90. 90.

    Perrier, C. et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm. Bowel Dis. 19, 246–253 (2013).

  91. 91.

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

  92. 92.

    Ordás, I., Feagan, B. G. & Sandborn, W. J. Early use of immunosuppressives or TNF antagonists for the treatment of Crohn’s disease: time for a change. Gut 60, 1754–1763 (2011).

  93. 93.

    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).

  94. 94.

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

  95. 95.

    Nalleweg, N. et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 64, 743–755 (2015).

  96. 96.

    Kobayashi, T. et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57, 1682–1689 (2008).

  97. 97.

    Kvedaraite, E. et al. Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD. Gut 65, 1632–1641 (2016).

  98. 98.

    Neurath, M. F. et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J. Exp. Med. 195, 1129–1143 (2002).

  99. 99.

    Leppkes, M. et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136, 257–267 (2009).

  100. 100.

    Aden, K. et al. Epithelial IL-23R signaling licenses protective IL-22 responses in intestinal inflammation. Cell Reports 16, 2208–2218 (2016).

  101. 101.

    Cox, J. H. et al. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol. 5, 99–109 (2012).

  102. 102.

    Maxwell, J. R. et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 43, 739–750 (2015).

  103. 103.

    Lee, J. S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).

  104. 104.

    Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology 153, 77–86.e76 (2017).

  105. 105.

    Feagan, B. G. et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389, 1699–1709 (2017).

  106. 106.

    Danne, C. et al. A large polysaccharide produced by Helicobacter hepaticus induces an anti-inflammatory gene signature in macrophages. Cell Host Microbe 22, 733–745.e735 (2017).

  107. 107.

    Brockmann, L. et al. Molecular and functional heterogeneity of IL-10-producing CD4+ T cells. Nat. Commun. 9, 5457 (2018).

  108. 108.

    Kühn, R., Löhler, J., Rennick, D., Rajewsky, K. & Müller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

  109. 109.

    Uhlig, H. H. et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J. Immunol. 177, 5852–5860 (2006).

  110. 110.

    Zigmond, E. et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40, 720–733 (2014).

  111. 111.

    Neumann, C. et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis. Nat. Immunol. 20, 471–481 (2019).

  112. 112.

    Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

  113. 113.

    Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000).

  114. 114.

    Braat, H., Peppelenbosch, M. P. & Hommes, D. W. Interleukin-10-based therapy for inflammatory bowel disease. Expert Opin. Biol. Ther. 3, 725–731 (2003).

  115. 115.

    Braat, H. et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin. Gastroenterol. Hepatol. 4, 754–759 (2006).

  116. 116.

    Powrie, F., Carlino, J., Leach, M. W., Mauze, S. & Coffman, R. L. A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 183, 2669–2674 (1996).

  117. 117.

    Fantini, M. C. et al. Transforming growth factor β induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 55, 671–680 (2006).

  118. 118.

    Monteleone, G. et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N. Engl. J. Med. 372, 1104–1113 (2015).

  119. 119.

    Feagan, B. G. et al. Effects of mongersen (GED-0301) on endoscopic and clinical outcomes in patients with active Crohn’s disease. Gastroenterology 154, 61–64.e66 (2018).

  120. 120.

    Spangler, J. B. et al. Antibodies to interleukin-2 elicit selective t cell subset potentiation through distinct conformational mechanisms. Immunity 42, 815–825 (2015).

  121. 121.

    Silva, D. A. et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature 565, 186–191 (2019).

  122. 122.

    Atreya, R. et al. Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis. Dig. Liver Dis. 50, 1019–1029 (2018).

  123. 123.

    Voskens, C. J. et al. Characterization and expansion of autologous GMP-ready regulatory T cells for TREG-based cell therapy in patients with ulcerative colitis. Inflamm. Bowel Dis. 23, 1348–1359 (2017).

  124. 124.

    Desreumaux, P. et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology 143, 1207–1217 (2012).

  125. 125.

    Leung, J.M. et al. IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue. Mucosal Immunol. 7, 124–133 (2014).

  126. 126.

    Pelczar, P. et al. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 354, 358–362 (2016).

  127. 127.

    Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

  128. 128.

    Aden, K. et al. ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J. Exp. Med. 215, 2868–2886 (2018).

  129. 129.

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

  130. 130.

    Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248.e231 (2011).

  131. 131.

    Naganuma, M. et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology 154, 935–947 (2018).

  132. 132.

    Chiriac, M. T. et al. Activation of epithelial signal transducer and activator of transcription 1 by interleukin 28 controls mucosal healing in mice with colitis and is increased in mucosa of patients with inflammatory bowel disease. Gastroenterology 153, 123–138.e8 (2017).

  133. 133.

    Biancheri, P. et al. Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease. Gastroenterology 149, 1564–1574.e3 (2015).

  134. 134.

    Atreya, R. & Neurath, M. F. Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease. Gastroenterol. Hepatol. 3, 790–802 (2018).

  135. 135.

    Belarif, L. et al. IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease. J. Clin. Invest. 130, 1910–1925 (2019).

  136. 136.

    Schmitt, H. et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut 68, 814–828 (2019).

  137. 137.

    Sandborn, W. J. et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367, 616–624 (2012).

  138. 138.

    Vermeire, S. et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 389, 266–275 (2017).

  139. 139.

    Popp, V. et al. Rectal delivery of a DNAzyme that specifically blocks the transcription factor GATA3 reduces colitis in mice. Gastroenterology 152, 176–192 (2017).

  140. 140.

    Withers, D. R. et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat. Med. 22, 319–323 (2016).

  141. 141.

    Colombel, J. F. et al. Adalimumab safety in global clinical trials of patients with Crohn’s disease. Inflamm. Bowel Dis. 15, 1308–1319 (2009).

  142. 142.

    Zundler, S. et al. The α4β1 homing pathway is essential for ileal homing of Crohn’s disease effector T cells in vivo. Inflamm. Bowel Dis. 23, 379–391 (2017).

  143. 143.

    Tillack, C. et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 63, 567–577 (2014).

  144. 144.

    Hanson, M. L. et al. Oral Delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology 146, 210–221.e213 (2014).

  145. 145.

    Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445 e437 (2019).

  146. 146.

    Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

  147. 147.

    Neurath, M. F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329–342 (2014).

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Acknowledgements

The research of M.F.N. was funded by the DFG (SFB1181, TRR241, FOR2438, SAOT graduate school), by the Interdisciplinary Centre for Clinical Research Erlangen and by the FAU Emerging Fields Initiative.

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Correspondence to Markus F. Neurath.

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M.F.N. has served as an advisor to Pentax, PPD, Abbvie, Boehringer, MSD, Janssen, Roche, Genentech, Shire and Takeda. M.F.N. received research support from Takeda, Boehringer, Roche and Shire.

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Fig. 1: Clinical features of IBD.
Fig. 2: Pathogenesis of IBD and targets for therapeutic interventions.
Fig. 3: T cell priming and trafficking in IBD.
Fig. 4: Immune cell subsets and cytokines in IBD.