Role of Th17 Cells in the Pathogenesis of Human IBD

The gastrointestinal tract plays a central role in immune system, being able to mount efficient immune responses against pathogens, keeping the homeostasis of the human gut. However, conditions like Crohn's disease (CD) or ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD), are related to an excessive and uncontrolled immune response against normal microbiota, through the activation of CD4+ T helper (Th) cells. Classically, IBD was thought to be primarily mediated by Th1 cells in CD or Th2 cells in UC, but it is now known that Th17 cells and their related cytokines are crucial mediators in both conditions. Th17 cells massively infiltrate the inflamed intestine of IBD patients, where they produce interleukin- (IL-) 17A and other cytokines, triggering and amplifying the inflammatory process. However, these cells show functional plasticity, and they can be converted into either IFN-γ producing Th1 cells or regulatory T cells. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut. Deeper insights into their plasticity in inflammatory conditions will contribute to advancing our understanding of the mechanisms that regulate mucosal homeostasis and inflammation in the gut, promoting the design of novel therapeutic approaches for IBD.

[1]  P. Loke,et al.  IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue , 2013, Mucosal Immunology.

[2]  L. Fitzpatrick.  Inhibition of IL-17 as a Pharmacological Approach for IBD , 2013, International reviews of immunology.

[3]  R. Cross,et al.  Combined blockade of IL-17A and IL-17F may prevent the development of experimental colitis. , 2013, Immunotherapy.

[4]  Li Yan,et al.  Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. , 2013, World Journal of Gastroenterology.

[5]  S. Poulsen,et al.  TH17 Cell Induction and Effects of IL-17A and IL-17F Blockade in Experimental Colitis , 2013, Inflammatory bowel diseases.

[6]  Jay K Kolls,et al.  The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. , 2013, Annual review of pathology.

[7]  A. Ammendola,et al.  Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study. , 2011, Journal of Crohn's & colitis.

[8]  G. Greenberg,et al.  Ustekinumab induction and maintenance therapy in refractory Crohn's disease. , 2012, The New England journal of medicine.

[9]  Francisco Guarner,et al.  The gut microbiota in IBD , 2012, Nature Reviews Gastroenterology &Hepatology.

[10]  R. D. Hatton,et al.  Reciprocal interactions of the intestinal microbiota and immune system , 2012, Nature.

[11]  L. Fitzpatrick,et al.  Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action , 2012, Journal of Pharmacology and Experimental Therapeutics.

[12]  M. T. Shata,et al.  Letter: pathogenicity of Th17 cells may differ in ulcerative colitis compared with Crohn's disease , 2012, Alimentary pharmacology & therapeutics.

[13]  Kristen L. Mueller,et al.  Is It Time for a Metagenomic Basis of Therapeutics? , 2012, Science.

[14]  T. Hohl,et al.  Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. , 2012, Immunity.

[15]  G. Núñez,et al.  Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine , 2012, The Journal of experimental medicine.

[16]  M. Jenkins,et al.  Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development , 2012, PLoS pathogens.

[17]  M. Comalada,et al.  The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice. , 2011, Biochemical pharmacology.

[18]  A. Rizzo,et al.  Involvement of interleukin-21 in the regulation of colitis-associated colon cancer , 2011, The Journal of experimental medicine.

[19]  C. Huttenhower,et al.  The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. , 2011, Cell host & microbe.

[20]  Vineet K. Sharma,et al.  Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of th17 cell differentiation. , 2011, Cell host & microbe.

[21]  G. Semenza,et al.  Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 , 2011, Cell.

[22]  L. Cosmi,et al.  Evidence of the transient nature of the Th17 phenotype of CD4+CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis. , 2011, Arthritis and rheumatism.

[23]  B. Pulendran,et al.  Functional Specializations of Intestinal Dendritic Cell and Macrophage Subsets That Control Th17 and Regulatory T Cell Responses Are Dependent on the T Cell/APC Ratio, Source of Mouse Strain, and Regional Localization , 2011, The Journal of Immunology.

[24]  Ateequr Rehman,et al.  Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. , 2011, Gastroenterology.

[25]  A. Rizzo,et al.  Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. , 2011, Gastroenterology.

[26]  R. Caspi,et al.  Faculty Opinions recommendation of Fate mapping of IL-17-producing T cells in inflammatory responses. , 2011 .

[27]  G. Eberl,et al.  Intestinal microbiota, evolution of the immune system and the bad reputation of pro‐inflammatory immunity , 2011, Cellular microbiology.

[28]  W. Strober,et al.  Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. , 2011, Gastroenterology.

[29]  C. Lees,et al.  Genetics of ulcerative colitis , 2011, Inflammatory bowel diseases.

[30]  Yoichiro Iwakura,et al.  Review Functional Specialization of Interleukin-17 Family Members , 2022 .

[31]  P. Miossec,et al.  Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes , 2011, Annals of the rheumatic diseases.

[32]  B. Sobral,et al.  Immunoregulatory mechanisms of macrophage PPAR γ in mice with experimental inflammatory bowel disease , 2010, Mucosal Immunology.

[33]  Bodo Grimbacher,et al.  Inflammatory bowel disease: is it a primary immunodeficiency? , 2011, Cellular and Molecular Life Sciences.

[34]  D. Laukens,et al.  Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease , 2010, BMC Immunology.

[35]  F. Pallone,et al.  Interleukin-21 triggers effector cell responses in the gut. , 2010, World Journal of Gastroenterology.

[36]  Stuart Adams,et al.  Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment , 2010, Proceedings of the National Academy of Sciences.

[37]  Fiona Powrie,et al.  An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer , 2010, The Journal of experimental medicine.

[38]  S. Mazmanian,et al.  Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis , 2010, Proceedings of the National Academy of Sciences.

[39]  J. Gordon,et al.  Homeostasis and Inflammation in the Intestine , 2010, Cell.

[40]  T. Yoshimoto,et al.  Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor , 2010, Proceedings of the National Academy of Sciences.

[41]  L. Cosmi,et al.  Evidence for a cross-talk between human neutrophils and Th17 cells. , 2010, Blood.

[42]  W. Paul,et al.  Heterogeneity and plasticity of T helper cells , 2010, Cell Research.

[43]  Dan R. Littman,et al.  Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria , 2009, Cell.

[44]  A. Bothwell,et al.  Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation , 2009, The Journal of Experimental Medicine.

[45]  A. Bothwell,et al.  Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation , 2009, The Journal of experimental medicine.

[46]  Annaïg Lan,et al.  The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. , 2009, Immunity.

[47]  Michael Famulok,et al.  The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity , 2009, The Journal of experimental medicine.

[48]  B. Stockinger,et al.  The aryl hydrocarbon receptor in immunity. , 2009, Trends in immunology.

[49]  Cynthia L Sears,et al.  A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses , 2009, Nature Medicine.

[50]  F. Sallusto,et al.  Heterogeneity of CD4+ memory T cells: Functional modules for tailored immunity , 2009, European journal of immunology.

[51]  H. Spits,et al.  Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells , 2009, Nature Immunology.

[52]  S. Gaffen.  Structure and signalling in the IL-17 receptor family , 2009, Nature Reviews Immunology.

[53]  R. Flavell,et al.  CD4 T-cell differentiation and inflammatory bowel disease. , 2009, Trends in molecular medicine.

[54]  Thomas Korn,et al.  IL-17 and Th17 Cells. , 2009, Annual review of immunology.

[55]  J. Blander,et al.  Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation , 2009, Nature.

[56]  D. Bending,et al.  Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. , 2009, The Journal of clinical investigation.

[57]  Yuka Kanno,et al.  Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. , 2009, Immunity.

[58]  C. Elson,et al.  Late developmental plasticity in the T helper 17 lineage. , 2009, Immunity.

[59]  L. Cosmi,et al.  TGF‐β indirectly favors the development of human Th17 cells by inhibiting Th1 cells , 2009, European journal of immunology.

[60]  Izortze Santin,et al.  TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin , 2009, Autoimmunity.

[61]  L. Kaer,et al.  Transforming growth factor is dispensable for the molecular orchestration of Th 17 cell differentiation , 2009 .

[62]  A. Murphy,et al.  Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. , 2008, Immunity.

[63]  L. Fouser,et al.  Th17 cytokines and their emerging roles in inflammation and autoimmunity , 2008, Immunological reviews.

[64]  R Balfour Sartor,et al.  Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. , 2008, Cell host & microbe.

[65]  Masahiro Yamamoto,et al.  ATP drives lamina propria TH17 cell differentiation , 2008, Nature.

[66]  R. Flavell,et al.  TGF-β: A Master of All T Cell Trades , 2008, Cell.

[67]  L. Cosmi,et al.  Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor , 2008, The Journal of experimental medicine.

[68]  T. Hibi,et al.  IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease , 2008, Gut.

[69]  A. Fischer,et al.  Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells , 2008, The Journal of experimental medicine.

[70]  David E. Anderson,et al.  IL-21 and TGF-β are required for differentiation of human TH17 cells , 2008, Nature.

[71]  T. Hibi,et al.  Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. , 2008, Journal of Clinical Investigation.

[72]  E. Barillot,et al.  A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses , 2008, Nature Immunology.

[73]  R. Broaddus,et al.  Regulation of inflammatory responses by IL-17F , 2008, The Journal of experimental medicine.

[74]  D. Littman,et al.  The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt , 2008, Nature Immunology.

[75]  Yuelei Shen,et al.  TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function , 2008, Nature.

[76]  J. Buer,et al.  The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins , 2008, Nature.

[77]  H. Weiner,et al.  Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor , 2008, Nature.

[78]  F. Powrie,et al.  Interleukin-23 Restrains Regulatory T Cell Activity to Drive T Cell-Dependent Colitis , 2008, Immunity.

[79]  W. Paul,et al.  Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome , 2008, Nature.

[80]  B. Müller-Myhsok,et al.  Role of the novel Th17 cytokine IL‐17F in inflammatory bowel disease (IBD): Upregulated colonic IL‐17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD , 2008, Inflammatory bowel diseases.

[81]  A. Rizzo,et al.  Regulation of gut inflammation and th17 cell response by interleukin-21. , 2008, Gastroenterology.

[82]  R. Xavier,et al.  IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. , 2008, The Journal of clinical investigation.

[83]  M. McGeachy,et al.  The link between IL-23 and Th17 cell-mediated immune pathologies. , 2007, Seminars in immunology.

[84]  Hiromu Ito,et al.  Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model , 2007, The Journal of experimental medicine.

[85]  O. Benada,et al.  Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells , 2007, Inflammatory bowel diseases.

[86]  Hua Yu,et al.  Cutting Edge: An In Vivo Requirement for STAT3 Signaling in TH17 Development and TH17-Dependent Autoimmunity1 , 2007, The Journal of Immunology.

[87]  D. Levy,et al.  IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways , 2007, Nature Immunology.

[88]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[89]  R. Noelle,et al.  All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation , 2007, The Journal of experimental medicine.

[90]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[91]  F. Sallusto,et al.  Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells , 2007, Nature Immunology.

[92]  R. Xavier,et al.  Unravelling the pathogenesis of inflammatory bowel disease , 2007, Nature.

[93]  A. D. Panopoulos,et al.  Essential autocrine regulation by IL-21 in the generation of inflammatory T cells , 2007, Nature.

[94]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[95]  W. Strober,et al.  Cutting Edge: Regulatory T Cells Induce CD4+CD25−Foxp3− T Cells or Are Self-Induced to Become Th17 Cells in the Absence of Exogenous TGF-β , 2007, The Journal of Immunology.

[96]  T. Mcclanahan,et al.  Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. , 2007, Gastroenterology.

[97]  Chen Dong,et al.  STAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells* , 2007, Journal of Biological Chemistry.

[98]  T. Macdonald,et al.  A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. , 2007, Gastroenterology.

[99]  A. D. Panopoulos,et al.  STAT 3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells * , 2007 .

[100]  T. Macdonald,et al.  WITHDRAWN: A Functional Role for Interleukin-21 in Promoting the Synthesis of the T Cell Chemoattractant, MIP-3α, by Gut Epithelial Cells , 2006 .

[101]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[102]  M. Neurath,et al.  Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. , 2006, Journal of immunology.

[103]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[104]  C. Coban,et al.  Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells , 2006, Nature Immunology.

[105]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[106]  Y. Sung,et al.  STAT3 and NF-κB Signal Pathway Is Required for IL-23-Mediated IL-17 Production in Spontaneous Arthritis Animal Model IL-1 Receptor Antagonist-Deficient Mice1 , 2006, The Journal of Immunology.

[107]  J. Kolls,et al.  Critical role of IL‐17 receptor signaling in acute TNBS‐induced colitis , 2006, Inflammatory bowel diseases.

[108]  R. D. Hatton,et al.  Transforming growth factor-beta induces development of the T(H)17 lineage. , 2006, Nature.

[109]  T. Mcclanahan,et al.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. , 2006, The Journal of clinical investigation.

[110]  F. Guarner,et al.  Mechanisms of Disease: the hygiene hypothesis revisited , 2006, Nature Clinical Practice Gastroenterology &Hepatology.

[111]  Clare Baecher-Allan,et al.  MHC Class II Expression Identifies Functionally Distinct Human Regulatory T Cells1 , 2006, The Journal of Immunology.

[112]  K. Herrmann,et al.  IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[113]  Yuka Kanno,et al.  T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription , 2006, The Journal of experimental medicine.

[114]  C. Manichanh,et al.  Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach , 2005, Gut.

[115]  R. D. Hatton,et al.  Transforming growth factor-beta induces development of the T(H)17 lineage. , 2006, Nature.

[116]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[117]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[118]  M. Zeitz,et al.  Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. , 2005, Gastroenterology.

[119]  T. Macdonald,et al.  Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. , 2005, Gastroenterology.

[120]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[121]  A. Andoh,et al.  Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. , 2004, Clinical immunology.

[122]  G. Bouma,et al.  The immunological and genetic basis of inflammatory bowel disease , 2003, Nature Reviews Immunology.

[123]  Y. Ho,et al.  Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop* , 2003, The Journal of Biological Chemistry.

[124]  A. Mowat,et al.  Anatomical basis of tolerance and immunity to intestinal antigens , 2003, Nature Reviews Immunology.

[125]  A. Gurney,et al.  Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17* , 2003, The Journal of Biological Chemistry.

[126]  A. Andoh,et al.  Increased expression of interleukin 17 in inflammatory bowel disease , 2003, Gut.

[127]  C. Mackay,et al.  T-cell function and migration. Two sides of the same coin. , 2000, The New England journal of medicine.

[128]  T. Sakaguchi,et al.  Claudins regulate the intestinal barrier in response to immune mediators. , 2000, Gastroenterology.

[129]  T. Martin,et al.  IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. , 1999, The Journal of clinical investigation.

[130]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[131]  R. de Waal Malefyt,et al.  Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. , 1998, The Journal of investigative dermatology.

[132]  J. Lafaille.  The role of helper T cell subsets in autoimmune diseases. , 1998, Cytokine & growth factor reviews.

[133]  H. Nomiyama,et al.  Identification of CCR6, the Specific Receptor for a Novel Lymphocyte-directed CC Chemokine LARC* , 1997, The Journal of Biological Chemistry.

[134]  S. Jonjić,et al.  Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes , 1989, The Journal of experimental medicine.