Intestinal epithelial cells: regulators of barrier function and immune homeostasis

The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host–microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host–commensal microbial relationships and immune cell homeostasis in the intestine.

[1]  P. Ricciardi-Castagnoli,et al.  Generation of Gut-Homing IgA-Secreting B Cells by Intestinal Dendritic Cells , 2006, Science.

[2]  Won-Jae Lee Bacterial-modulated host immunity and stem cell activation for gut homeostasis. , 2009, Genes & development.

[3]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[4]  Shizuo Akira,et al.  Dissecting negative regulation of Toll-like receptor signaling. , 2012, Trends in immunology.

[5]  P. Godowski,et al.  Cutting Edge: Bacterial Flagellin Activates Basolaterally Expressed TLR5 to Induce Epithelial Proinflammatory Gene Expression1 , 2001, The Journal of Immunology.

[6]  A. Rivollier,et al.  Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon , 2012, The Journal of experimental medicine.

[7]  F. Nestle,et al.  Faculty Opinions recommendation of Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. , 2010 .

[8]  Matthew S. Lewis,et al.  Profound early control of highly pathogenic SIV by an effector-memory T cell vaccine , 2011, Nature.

[9]  K. Berer,et al.  Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination , 2011, Nature.

[10]  C. Drachenberg,et al.  TGF-β–dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease , 2005, The Journal of experimental medicine.

[11]  F. Johansen,et al.  Regulation of the polymeric immunoglobulin receptor by the classical and alternative NF-κB pathways in intestinal epithelial cells , 2011, Mucosal Immunology.

[12]  Judy H Cho,et al.  Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis , 2007, Nature Genetics.

[13]  R. Xu,et al.  Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. , 2007, Gastroenterology.

[14]  D. Brenner,et al.  Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response , 2009, Proceedings of the National Academy of Sciences.

[15]  K. Honda,et al.  Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species , 2011, Science.

[16]  Marshall H. Montrose,et al.  Caveolin-1–dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo , 2010, The Journal of cell biology.

[17]  Julian Lewis,et al.  Organizing cell renewal in the intestine: stem cells, signals and combinatorial control , 2006, Nature Reviews Genetics.

[18]  J. Meijerink,et al.  Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. , 2006, Gastroenterology.

[19]  F. Johansen,et al.  Regulation of the polymeric immunoglobulin receptor and IgA transport: New advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity , 2011, Mucosal Immunology.

[20]  Zhijian J. Chen,et al.  Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis , 2011, Proceedings of the National Academy of Sciences.

[21]  R. Sumpter,et al.  Intestinal epithelial autophagy is essential for host defense against invasive bacteria. , 2013, Cell host & microbe.

[22]  Kan Yang,et al.  Colorectal Cancer in Mice Genetically Deficient in the Mucin Muc2 , 2002, Science.

[23]  G. Gerken,et al.  Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. , 2009, Gastroenterology.

[24]  A. Murphy,et al.  Goblet Cell-Derived Resistin-Like Molecule β Augments CD4+ T Cell Production of IFN-γ and Infection-Induced Intestinal Inflammation1 , 2008, The Journal of Immunology.

[25]  N. Salzman,et al.  Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis , 2011, Nature Reviews Microbiology.

[26]  B. Nardelli,et al.  DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL , 2002, Nature Immunology.

[27]  Thomas Lengauer,et al.  A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 , 2007, Nature Genetics.

[28]  Shinichiro Sawa,et al.  Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. , 2008, Immunity.

[29]  Y. Belkaid,et al.  Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid , 2007, The Journal of experimental medicine.

[30]  F. Ginhoux,et al.  Origin of the lamina propria dendritic cell network. , 2009, Immunity.

[31]  A. Neish,et al.  The bacterial fermentation product butyrate influences epithelial signaling via reactive oxygen species-mediated changes in cullin-1 neddylation , 2009, The Journal of Immunology.

[32]  M. Hornef,et al.  Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells , 2006, The Journal of experimental medicine.

[33]  A. Ouellette,et al.  Positional specificity of defensin gene expression reveals Paneth cell heterogeneity in mouse small intestine. , 1996, The American journal of physiology.

[34]  D. Artis,et al.  Innate lymphoid cells: balancing immunity, inflammation, and tissue repair in the intestine. , 2012, Cell host & microbe.

[35]  F. Bushman,et al.  Innate Lymphoid Cells Promote Anatomical Containment of Lymphoid-Resident Commensal Bacteria , 2012, Science.

[36]  D. Beier,et al.  Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. , 1999, Journal of immunology.

[37]  Eric Vivier,et al.  Innate lymphoid cells — a proposal for uniform nomenclature , 2013, Nature Reviews Immunology.

[38]  R. Kastelein,et al.  Commensal-dependent expression of IL-25 regulates the IL-23–IL-17 axis in the intestine , 2008, The Journal of experimental medicine.

[39]  R. Xavier,et al.  Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine , 2010, Cell.

[40]  Jonathan R. Brestoff,et al.  IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells , 2013, The Journal of experimental medicine.

[41]  M. Capecchi,et al.  The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations , 2011, Proceedings of the National Academy of Sciences.

[42]  M. Chamaillard,et al.  Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury , 2011, Proceedings of the National Academy of Sciences.

[43]  Michael Grabe,et al.  Antibacterial membrane attack by a pore-forming intestinal C-type lectin , 2013, Nature.

[44]  Fumio Takei,et al.  Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. , 2012, Immunity.

[45]  M. Karin,et al.  Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation , 2011, The Journal of experimental medicine.

[46]  Steffen Jung,et al.  Intestinal lamina propria dendritic cell subsets have different origin and functions. , 2009, Immunity.

[47]  P. Ricciardi-Castagnoli,et al.  Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria , 2001, Nature Immunology.

[48]  Steffen Jung,et al.  Intestinal macrophages: well educated exceptions from the rule. , 2013, Trends in immunology.

[49]  M. Neurath,et al.  Epithelial NEMO links innate immunity to chronic intestinal inflammation , 2007, Nature.

[50]  Richard A. Flavell,et al.  Nod2-Dependent Regulation of Innate and Adaptive Immunity in the Intestinal Tract , 2005, Science.

[51]  Yu-Tseung Liu,et al.  Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells , 2006, Nature Cell Biology.

[52]  Chi-Bin Chien,et al.  Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia , 2012, Nature.

[53]  P. Krajči,et al.  Absence of Epithelial Immunoglobulin a Transport, with Increased Mucosal Leakiness, in Polymeric Immunoglobulin Receptor/Secretory Component–Deficient Mice , 1999, The Journal of experimental medicine.

[54]  Maria T. Abreu,et al.  Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function , 2010, Nature Reviews Immunology.

[55]  A. Kaser,et al.  Paneth cells as a site of origin for intestinal inflammation , 2013, Nature.

[56]  A. Cerutti The regulation of IgA class switching , 2008, Nature Reviews Immunology.

[57]  P. Sansonetti,et al.  Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment , 2011, EMBO molecular medicine.

[58]  A. Gruber,et al.  Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis , 2007, Nature.

[59]  M. Teitell,et al.  Mucosal CD8 Memory T Cells are selected in the periphery by an MHC Class I Molecule , 2011, Nature Immunology.

[60]  L. Hooper,et al.  Epithelial antimicrobial defence of the skin and intestine , 2012, Nature Reviews Immunology.

[61]  H. Clevers,et al.  Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties , 2013, Cell.

[62]  S. Travis,et al.  IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease , 2011, The Journal of experimental medicine.

[63]  L. Eckmann,et al.  Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface , 2008, Proceedings of the National Academy of Sciences.

[64]  L. N. Fink,et al.  Epithelial cells prime the immune response to an array of gut‐derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor‐β , 2007, Immunology.

[65]  F. Bushman,et al.  Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis , 2013, Nature.

[66]  J. Schulzke,et al.  Altered permeability in inflammatory bowel disease: pathophysiology and clinical implications , 2007, Current opinion in gastroenterology.

[67]  Scott N. Mueller,et al.  Peripheral tissue surveillance and residency by memory T cells. , 2013, Trends in immunology.

[68]  F. Powrie,et al.  Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model , 2013, The Journal of experimental medicine.

[69]  E. Elinav,et al.  Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4 , 2010, Proceedings of the National Academy of Sciences.

[70]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[71]  Ya-Jen Chang,et al.  Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity , 2011, Nature Immunology.

[72]  C. Weber,et al.  Dynamic migration of γδ intraepithelial lymphocytes requires occludin , 2012, Proceedings of the National Academy of Sciences.

[73]  Judy H. Cho,et al.  [Letters to Nature] , 1975, Nature.

[74]  B. Biteau,et al.  Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. , 2011, Cell stem cell.

[75]  D. Green,et al.  The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. , 2011, Cancer cell.

[76]  J. Magarian Blander,et al.  Detection of prokaryotic mRNA signifies microbial viability and promotes immunity , 2011, Nature.

[77]  Francis J. Huber,et al.  IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine , 2012, Nature.

[78]  Gisen Kim,et al.  Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis , 2009, Nature Immunology.

[79]  R. Ley,et al.  Innate immunity and intestinal microbiota in the development of Type 1 diabetes , 2008, Nature.

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

[81]  M. Sykes,et al.  Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. , 2013, Immunity.

[82]  A. Macpherson,et al.  Induction of Protective IgA by Intestinal Dendritic Cells Carrying Commensal Bacteria , 2004, Science.

[83]  N. Murthy,et al.  Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases , 2011, Proceedings of the National Academy of Sciences.

[84]  Sang-Uk Seo,et al.  Role of the gut microbiota in immunity and inflammatory disease , 2013, Nature Reviews Immunology.

[85]  D. Taupin,et al.  Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[86]  P. Allavena,et al.  Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells , 2005, Nature Immunology.

[87]  M. Kagnoff,et al.  RIG-I/MDA5/MAVS Are Required To Signal a Protective IFN Response in Rotavirus-Infected Intestinal Epithelium , 2011, The Journal of Immunology.

[88]  Scott N. Mueller,et al.  Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation , 2012, Proceedings of the National Academy of Sciences.

[89]  Tsutomu Takeuchi,et al.  Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells , 2009, Nature.

[90]  A. Ding,et al.  Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI , 2007, Nature Immunology.

[91]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[92]  Grace Y Chen,et al.  Inflammasomes in intestinal inflammation and cancer. , 2011, Gastroenterology.

[93]  R. Geha,et al.  TACI is mutant in common variable immunodeficiency and IgA deficiency , 2005, Nature Genetics.

[94]  F. Marincola,et al.  MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18 , 2010, The Journal of experimental medicine.

[95]  M. Lazar,et al.  RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[96]  Ta-Chiang Liu,et al.  Genetics and Pathogenesis of Inflammatory Bowel Disease. , 2016, Annual review of pathology.

[97]  Y. S. Kim,et al.  Intestinal Goblet Cells and Mucins in Health and Disease: Recent Insights and Progress , 2010, Current gastroenterology reports.

[98]  R. Medzhitov,et al.  Regulation of Spontaneous Intestinal Tumorigenesis Through the Adaptor Protein MyD88 , 2007, Science.

[99]  R. Kastelein,et al.  IL-25 elicits a multi-potent progenitor cell population that promotes Th2 cytokine responses , 2010, Nature.

[100]  M. Hepworth,et al.  TSLP Elicits IL-33–Independent Innate Lymphoid Cell Responses to Promote Skin Inflammation , 2013, Science Translational Medicine.

[101]  H. Clevers,et al.  Stem cells, self-renewal, and differentiation in the intestinal epithelium. , 2009, Annual review of physiology.

[102]  O. Pabst,et al.  The puzzle of intestinal lamina propria dendritic cells and macrophages , 2010, European journal of immunology.

[103]  T. Denning,et al.  Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis. , 2012, Immunity.

[104]  M. Lamkanfi,et al.  The Nlrp3 inflammasome: contributions to intestinal homeostasis. , 2011, Trends in immunology.

[105]  A. Iwasaki,et al.  A vaccine strategy protects against genital herpes by establishing local memory T cells , 2012, Nature.

[106]  H. Tilg,et al.  XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease , 2008, Cell.

[107]  David Artis,et al.  Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus , 2011, Nature Immunology.

[108]  R. Xavier,et al.  Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor–κB activation in muramyl dipeptide recognition , 2005, The Journal of cell biology.

[109]  D. Artis,et al.  TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis , 2009, The Journal of experimental medicine.

[110]  M. Pasparakis,et al.  Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor–induced toxicity and experimental colitis , 2010, The Journal of experimental medicine.

[111]  C. Buskens,et al.  Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues , 2013, Nature Immunology.

[112]  Hilde Cheroutre,et al.  The light and dark sides of intestinal intraepithelial lymphocytes , 2011, Nature Reviews Immunology.

[113]  Christophe Benoist,et al.  Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. , 2010, Immunity.

[114]  A. Plebani,et al.  Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. , 2007, Immunity.

[115]  G. Eberl,et al.  RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota , 2011, Nature Immunology.

[116]  J. Epstein,et al.  Interconversion Between Intestinal Stem Cell Populations in Distinct Niches , 2011, Science.

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

[118]  D. Artis,et al.  Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung. , 2012, Current opinion in immunology.

[119]  C. Pothoulakis,et al.  Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[120]  Rodney D. Newberry,et al.  Goblet cells deliver luminal antigen to CD103+ DCs in the small intestine , 2012, Nature.

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

[122]  C. Reutelingsperger,et al.  Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. , 2013, The Journal of clinical investigation.

[123]  F. Powrie,et al.  Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans , 2008, The Journal of experimental medicine.

[124]  D. Ito,et al.  Intestinal Epithelial Cell-Derived Semaphorin 7A Negatively Regulates Development of Colitis via αvβ1 Integrin , 2012, The Journal of Immunology.

[125]  K. Honda,et al.  Transcriptional Reprogramming of Mature CD4+ T helper Cells generates distinct MHC class II-restricted Cytotoxic T Lymphocytes , 2013, Nature Immunology.

[126]  G. Gerken,et al.  Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. , 2004, Gastroenterology.

[127]  N. Beauchemin,et al.  Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. , 2010, Immunity.

[128]  J. Lambeth,et al.  Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox‐mediated generation of reactive oxygen species , 2013, The EMBO journal.

[129]  C. Blobel,et al.  MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands , 2010, Proceedings of the National Academy of Sciences.

[130]  M. Teitell,et al.  Mucosal memory CD 8 + T cells are selected in the periphery by an MHC class I molecule , 2011 .

[131]  J. Turner,et al.  Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease , 2006, Laboratory Investigation.

[132]  Liping Su,et al.  Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. , 2009, Gastroenterology.

[133]  G. Eberl,et al.  Development and function of intestinal innate lymphoid cells. , 2012, Current opinion in immunology.

[134]  D. Podolsky,et al.  Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. , 2004, Gastroenterology.

[135]  C. A. de la Motte,et al.  The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. , 2007, Immunity.

[136]  W. Agace,et al.  Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions , 2009, The Journal of experimental medicine.

[137]  M. Hornef,et al.  miR-146a mediates protective innate immune tolerance in the neonate intestine. , 2010, Cell host & microbe.

[138]  R. Jenq,et al.  Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. , 2012, Immunity.

[139]  J. Magarian Blander,et al.  Beyond pattern recognition: five immune checkpoints for scaling the microbial threat , 2012, Nature Reviews Immunology.

[140]  Hergen Spits,et al.  Innate lymphoid cells: emerging insights in development, lineage relationships, and function. , 2012, Annual review of immunology.

[141]  C. Ziegler,et al.  Thymic stromal lymphopoietin-mediated extramedullary hematopoiesis promotes allergic inflammation. , 2013, Immunity.

[142]  Yong-ping Su,et al.  Active deformation of apoptotic intestinal epithelial cells with adhesion-restricted polarity contributes to apoptotic clearance , 2011, Laboratory Investigation.

[143]  兪 慶声 MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8αα TCRαβ and TCRγδ intestinal intraepithelial lymphocytes , 2008 .

[144]  A. Schäffer,et al.  Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans , 2005, Nature Genetics.

[145]  David J. Erle,et al.  Systemically dispersed innate IL-13–expressing cells in type 2 immunity , 2010, Proceedings of the National Academy of Sciences.

[146]  I. Weissman,et al.  Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. , 1997, Immunity.

[147]  D. Douek,et al.  Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. , 2011, Gastroenterology.

[148]  R. Ley,et al.  The Antibacterial Lectin RegIIIγ Promotes the Spatial Segregation of Microbiota and Host in the Intestine , 2011, Science.

[149]  A. Macpherson,et al.  Interactions Between the Microbiota and the Immune System , 2012, Science.

[150]  H. Herfarth,et al.  NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. , 2012, Immunity.

[151]  Hidde L Ploegh,et al.  CX3CR1-Mediated Dendritic Cell Access to the Intestinal Lumen and Bacterial Clearance , 2005, Science.

[152]  Jeffrey I. Gordon,et al.  Angiogenins: a new class of microbicidal proteins involved in innate immunity , 2003, Nature Immunology.

[153]  A. Young,et al.  Prokaryotic Regulation of Epithelial Responses by Inhibition of IκB-α Ubiquitination , 2000 .

[154]  R. Geha,et al.  TACI and BAFF-R mediate isotype switching in B cells , 2005, The Journal of experimental medicine.

[155]  J. Ferrières,et al.  Metabolic Endotoxemia Initiates Obesity and Insulin Resistance , 2007, Diabetes.

[156]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[157]  D. Artis,et al.  CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. , 2011, Immunity.

[158]  A. McKenzie,et al.  Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity , 2010, Nature.

[159]  Werner Müller,et al.  Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. , 2011, Immunity.

[160]  U. Pannicke,et al.  Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt(+) innate lymphocytes. , 2010, Immunity.

[161]  R. Hilgarth,et al.  IFN-γ and TNF-α induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling , 2012, Mucosal Immunology.

[162]  R. Germain,et al.  Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement , 2006, The Journal of experimental medicine.

[163]  M. Colonna,et al.  Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. , 2013, Immunity.

[164]  E. Elinav,et al.  Integrative inflammasome activity in the regulation of intestinal mucosal immune responses , 2012, Mucosal Immunology.

[165]  A. McKenzie,et al.  Innate lymphoid cells — how did we miss them? , 2013, Nature Reviews Immunology.

[166]  William W. Agace,et al.  Functional specialization of gut CD103 dendritic cells in the regulation of tissue-selective T cell homing , 2005 .

[167]  P. Matzinger The Danger Model: A Renewed Sense of Self , 2002, Science.

[168]  Keiichiro Suzuki,et al.  Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[169]  P. Rosenstiel,et al.  RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition , 2012, Proceedings of the National Academy of Sciences.

[170]  K. Honda,et al.  The microbiome in infectious disease and inflammation. , 2012, Annual review of immunology.

[171]  Lena Holm,et al.  The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria , 2010, Gut microbes.

[172]  Burkhard Becher,et al.  IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells , 2012, The Journal of experimental medicine.

[173]  N A Mabbott,et al.  Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium , 2013, Mucosal Immunology.

[174]  J. Mora,et al.  Differentiation and homing of IgA-secreting cells , 2008, Mucosal Immunology.

[175]  K. Rajewsky,et al.  Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. , 2011, The Journal of clinical investigation.

[176]  H. Lochs,et al.  Intestinal permeability and the prediction of relapse in Crohri's disease , 1993, The Lancet.

[177]  Sarah L. Brown,et al.  A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells , 2008, Nature.

[178]  A. Morgun,et al.  Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut , 2011, Nature Medicine.

[179]  L. Thim,et al.  Trefoil peptides promote epithelial migration through a transforming growth factor beta-independent pathway. , 1994, The Journal of clinical investigation.

[180]  Hergen Spits,et al.  The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. , 2012, Immunity.

[181]  Jongdae Lee,et al.  ERK activation drives intestinal tumorigenesis in Apcmin/+ mice , 2010, Nature Medicine.

[182]  M. Hornef,et al.  Secreted enteric antimicrobial activity localises to the mucus surface layer , 2008, Gut.

[183]  Si-young Song,et al.  Retinoic acid imprints gut-homing specificity on T cells. , 2004, Immunity.

[184]  M. Ishii,et al.  Intestinal CX3C chemokine receptor 1high (CX3CR1high) myeloid cells prevent T-cell-dependent colitis , 2012, Proceedings of the National Academy of Sciences.

[185]  Bihui Huang,et al.  Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals , 2013, Science.

[186]  A. DeFranco,et al.  γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface , 2011, Proceedings of the National Academy of Sciences.

[187]  Shunsuke Kimura,et al.  Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response , 2009, Nature.

[188]  B. Vickery,et al.  TSLP Promotes Interleukin-3-independent Basophil Haematopoiesis and Type 2 Inflammation , 2012, Pediatrics.

[189]  G. Corrao,et al.  Intestinal permeability test as a predictor of clinical course in Crohn's disease , 1999, American Journal of Gastroenterology.

[190]  C. Loddenkemper,et al.  Interleukin (IL)-23 mediates Toxoplasma gondii–induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17 , 2009, The Journal of experimental medicine.

[191]  T. Stappenbeck,et al.  Viral interactions with the host and microbiota in the intestine , 2012, Current Opinion in Immunology.

[192]  Michael Karin,et al.  IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer , 2004, Cell.

[193]  J. Brenchley,et al.  Microbial translocation is a cause of systemic immune activation in chronic HIV infection , 2006, Retrovirology.

[194]  Wolfgang Weninger,et al.  Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells , 2003, Nature.