The Intestinal Immune System During Homeostasis and Inflammatory Bowel Disease

  • David A. HillEmail author
  • William A. FaubionJr


The mucosa and associated lymphoid tissues of the gastrointestinal tract contain one of the most diverse and complicated immunologic systems in the human body. With an immense antigenic exposure, this system has the daunting task of distinguishing between beneficial, inert, and pathogenic molecules and microorganisms with the goals of maintaining mucosal homeostasis and providing appropriate and necessary defense, all while allowing for the absorption of nutrients essential for life. It is perhaps not surprising then that a breakdown in the normal functions of the intestinal immune system results in a wide variety of disease states. One of the quintessential examples of failure of the intestinal immune system is inflammatory bowel disease (IBD). In this chapter, we review the innate and adaptive components of the intestinal immune system with particular attention to unique features in children. We also highlight key insights into how the intestinal immune system contributes to IBD pathogenesis.


Innate Adaptive Immune system Inflammatory bowel disease Colitis Commensal bacteria 


  1. 1.
    MacDonald TT, Spencer J, Viney JL, Williams CB, Walker-Smith JA. Selective biopsy of human Peyer’s patches during ileal endoscopy. Gastroenterology. 1987;93:1356–62. doi: S0016508587003330 [pii]PubMedCrossRefGoogle Scholar
  2. 2.
    Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003;3:331–41. doi: 10.1038/nri1057.PubMedCrossRefGoogle Scholar
  3. 3.
    Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol. 2008;1:11–22. doi: 10.1038/mi.2007.6.PubMedCrossRefGoogle Scholar
  4. 4.
    Hill DA, Artis D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol. 2010;28:623–67. doi: 10.1146/annurev-immunol-030409-101330.PubMedCrossRefGoogle Scholar
  5. 5.
    Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it ever too old to become young again? Nat Rev Immunol. 2009;9:57–62. doi: 10.1038/nri2471.PubMedCrossRefGoogle Scholar
  6. 6.
    Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9:799–809. doi: 10.1038/nri2653.PubMedCrossRefGoogle Scholar
  7. 7.
    Mukherjee S, Hooper LV. Antimicrobial defense of the intestine. Immunity. 2015;42:28–39. doi: 10.1016/j.immuni.2014.12.028.PubMedCrossRefGoogle Scholar
  8. 8.
    Pelaseyed T, Bergstrom JH, Gustafsson JK, Ermund A, Birchenough GM, Schutte A, van der Post S, Svensson F, Rodriguez-Pineiro AM, Nystrom EE, Wising C, Johansson ME, Hansson GC. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;260:8–20. doi: 10.1111/imr.12182.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Udall JN, Pang K, Fritze L, Kleinman R, Walker WA. Development of gastrointestinal mucosal barrier. I. The effect of age on intestinal permeability to macromolecules. Pediatr Res. 1981;15:241–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Schulz O, Pabst O. Antigen sampling in the small intestine. Trends Immunol. 2013;34:155–61. doi: 10.1016/ Scholar
  11. 11.
    Prescott D, Lee J, Philpott DJ. An epithelial armamentarium to sense the microbiota. Semin Immunol. 2013;25:323–33. doi: 10.1016/j.smim.2013.09.007.PubMedCrossRefGoogle Scholar
  12. 12.
    Hershberg RM, Mayer LF. Antigen processing and presentation by intestinal epithelial cells – polarity and complexity. Immunol Today. 2000;21:123–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Shao L, Kamalu O, Mayer L. Non-classical MHC class I molecules on intestinal epithelial cells: mediators of mucosal crosstalk. Immunol Rev. 2005;206:160–76. doi: IMR295 [pii]PubMedCrossRefGoogle Scholar
  14. 14.
    Coskun M. Intestinal epithelium in inflammatory bowel disease. Front Med (Lausanne). 2014;1:24. doi: 10.3389/fmed.2014.00024.Google Scholar
  15. 15.
    Boltin D, Perets TT, Vilkin A, Niv Y. Mucin function in inflammatory bowel disease: an update. J Clin Gastroenterol. 2013;47:106–11. doi: 10.1097/MCG.0b013e3182688e73.PubMedCrossRefGoogle Scholar
  16. 16.
    Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C. Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature. 2011;477:335–9. doi: 10.1038/nature10400.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Kiesslich R, Duckworth CA, Moussata D, Gloeckner A, Lim LG, Goetz M, Pritchard DM, Galle PR, Neurath MF, Watson AJ. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut. 2012;61:1146–53. doi: 10.1136/gutjnl-2011-300695.PubMedCrossRefGoogle Scholar
  18. 18.
    Lim LG, Neumann J, Hansen T, Goetz M, Hoffman A, Neurath MF, Galle PR, Chan YH, Kiesslich R, Watson AJ. Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2014;20:892–900. doi: 10.1097/MIB.0000000000000027.PubMedCrossRefGoogle Scholar
  19. 19.
    Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015;12:205–17. doi: 10.1038/nrgastro.2015.34.PubMedCrossRefGoogle Scholar
  20. 20.
    Lecuyer E, Rakotobe S, Lengline-Garnier H, Lebreton C, Picard M, Juste C, Fritzen R, Eberl G, McCoy KD, Macpherson AJ, Reynaud CA, Cerf-Bensussan N, Gaboriau-Routhiau V. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity. 2014;40:608–20. doi: 10.1016/j.immuni.2014.03.009.PubMedCrossRefGoogle Scholar
  21. 21.
    He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J, Shan M, Chadburn A, Villanacci V, Plebani A, Knowles DM, Rescigno M, Cerutti A. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity. 2007;26:812–26. doi: 10.1016/j.immuni.2007.04.014.PubMedCrossRefGoogle Scholar
  22. 22.
    Xu W, He B, Chiu A, Chadburn A, Shan M, Buldys M, Ding A, Knowles DM, Santini PA, Cerutti A. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat Immunol. 2007;8:294–303. doi: 10.1038/ni1434.PubMedCrossRefGoogle Scholar
  23. 23.
    Browning BL, Huebner C, Petermann I, Gearry RB, Barclay ML, Shelling AN, Ferguson LR. Has toll-like receptor 4 been prematurely dismissed as an inflammatory bowel disease gene? Association study combined with meta-analysis shows strong evidence for association. Am J Gastroenterol. 2007;102:2504–12. doi: AJG1463 [pii]PubMedCrossRefGoogle Scholar
  24. 24.
    Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J, Rutgeerts P. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut. 2004;53:987–92.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Torok HP, Glas J, Tonenchi L, Mussack T, Folwaczny C. Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. Clin Immunol. 2004;112:85–91. doi: 10.1016/j.clim.2004.03.002.PubMedCrossRefGoogle Scholar
  26. 26.
    Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000;68:7010–7.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Frolova L, Drastich P, Rossmann P, Klimesova K, Tlaskalova-Hogenova H. Expression of Toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. J Histochem Cytochem. 2008;56:267–74. doi: jhc.7A7303.2007 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Hausmann M, Kiessling S, Mestermann S, Webb G, Spottl T, Andus T, Scholmerich J, Herfarth H, Ray K, Falk W, Rogler G. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology. 2002;122:1987–2000. doi: S001650850200032X [pii]PubMedCrossRefGoogle Scholar
  29. 29.
    Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, Totsuka T, Takeda K, Akira S, Watanabe M. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J Gastroenterol. 2005;40:16–23. doi: 10.1007/s00535-004-1492-9.PubMedCrossRefGoogle Scholar
  30. 30.
    Saxena M, Yeretssian G. NOD-like receptors: master regulators of inflammation and cancer. Front Immunol. 2014;5:327. doi: 10.3389/fimmu.2014.00327.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, International IBD Genetics Consortium (IIBDGC), Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. doi: 10.1038/nature11582.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hedl M, Li J, Cho JH, Abraham C. Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci U S A. 2007;104:19440–5. doi: 10.1073/pnas.0706097104.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kullberg BJ, Ferwerda G, de Jong DJ, Drenth JP, Joosten LA, Van der Meer JW, Netea MG. Crohn’s disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli. Immunology. 2008;123:600–5. doi: IMM2735 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, Kambayashi T, Larosa DF, Renner ED, Orange JS, Bushman FD, Artis D. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med. 2012;25:18(4):538–46. doi: 10.1038/nm.2657.
  35. 35.
    Hanai H, Takeuchi K, Iida T, Kashiwagi N, Saniabadi AR, Matsushita I, Sato Y, Kasuga N, Nakamura T. Relationship between fecal calprotectin, intestinal inflammation, and peripheral blood neutrophils in patients with active ulcerative colitis. Dig Dis Sci. 2004;49:1438–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Boppana NB, Devarajan A, Gopal K, Barathan M, Bakar SA, Shankar EM, Ebrahim AS, Farooq SM. Blockade of CXCR2 signalling: a potential therapeutic target for preventing neutrophil-mediated inflammatory diseases. Exp Biol Med (Maywood). 2014;239:509–18. doi: 10.1177/1535370213520110.CrossRefGoogle Scholar
  37. 37.
    Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B, Lees W, Novelli M, Bloom S, Segal AW. Defective acute inflammation in Crohn’s disease: a clinical investigation. Lancet. 2006;367:668–78. doi: S0140-6736(06)68265-2 [pii]PubMedCrossRefGoogle Scholar
  38. 38.
    Kelsen JR, Rosh J, Heyman M, Winter HS, Ferry G, Cohen S, Mamula P, Baldassano RN. PhaseI trial of sargramostim in pediatric Crohn’s disease Inflamm Bowel Dis. 2010;16(7):1203–8. doi: 10.1002/ibd.21204.
  39. 39.
    Roth L, Macdonald JK, McDonald JW, Chande N. Sargramostim (GM-CSF) for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2011;(11):CD008538. doi:CD008538.  10.1002/14651858.CD008538.pub2.
  40. 40.
    Rugtveit J, Bakka A, Brandtzaeg P. Differential distribution of B7.1 (CD80) and B7.2 (CD86) costimulatory molecules on mucosal macrophage subsets in human inflammatory bowel disease (IBD). Clin Exp Immunol. 1997;110:104–13.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Smith PD, Smythies LE, Mosteller-Barnum M, Sibley DA, Russell MW, Merger M, Sellers MT, Orenstein JM, Shimada T, Graham MF, Kubagawa H. Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol. 2001;167:2651–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Kuhl AA, Erben U, Kredel LI, Siegmund B. Diversity of Intestinal Macrophages in Inflammatory Bowel Diseases. Front Immunol. 2015;6:613. doi: 10.3389/fimmu.2015.00613.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Smith PD, Smythies LE, Shen R, Greenwell-Wild T, Gliozzi M, Wahl SM. Intestinal macrophages and response to microbial encroachment. Mucosal Immunol. 2011;4:31–42. doi: 10.1038/mi.2010.66.PubMedCrossRefGoogle Scholar
  44. 44.
    Schenk M, Bouchon A, Birrer S, Colonna M, Mueller C. Macrophages expressing triggering receptor expressed on myeloid cells-1 are underrepresented in the human intestine. J Immunol. 2005;174:517–24. doi: 174/1/517 [pii]PubMedCrossRefGoogle Scholar
  45. 45.
    Smythies LE, Shen R, Bimczok D, Novak L, Clements RH, Eckhoff DE, Bouchard P, George MD, Hu WK, Dandekar S, Smith PD. Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation. J Biol Chem. 2010;285:19593–604. doi: 10.1074/jbc.M109.069955.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Thiesen S, Janciauskiene S, Uronen-Hansson H, Agace W, Hogerkorp CM, Spee P, Hakansson K, Grip O. CD14(hi)HLA-DR(dim) macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn’s disease. J Leukoc Biol. 2014;95:531–41. doi: 10.1189/jlb.0113021.PubMedCrossRefGoogle Scholar
  47. 47.
    Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T, Sakuraba A, Kitazume MT, Sugita A, Koganei K, Akagawa KS, Hibi T. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest. 2008;118:2269–80. doi: 10.1172/JCI34610.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, Baeuerle PA, Scholmerich J, Gross V. Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology. 1998;115:357–69. doi: S001650859800136X [pii]PubMedCrossRefGoogle Scholar
  49. 49.
    Schenk M, Bouchon A, Seibold F, Mueller C. TREM-1--expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest. 2007;117:3097–106. doi: 10.1172/JCI30602.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kugathasan S, Werlin SL, Martinez A, Rivera MT, Heikenen JB, Binion DG. Prolonged duration of response to infliximab in early but not late pediatric Crohn’s disease. Am J Gastroenterol. 2000;95(11):3189–94.Google Scholar
  51. 51.
    Lahad A, Weiss B. Current therapy of pediatric Crohn’s disease. World J Gastrointest Pathophysiol. 2015;6:33–42. doi: 10.4291/wjgp.v6.i2.33.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Khanna R, Preiss JC, MacDonald JK, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2015;5(5):CD007572. doi: 10.1002/14651858.CD007572.pub2.
  53. 53.
    Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL, Quezado M, Yang Z, Neurath MF, Salfeld J, Veldman GM, Schwertschlag U, Strober W, Anti-IL-12 Crohn’s Disease Study Group. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med. 2004;351:2069–79. doi: 351/20/2069 [pii]PubMedCrossRefGoogle Scholar
  54. 54.
    Monteleone G, Boirivant M, Pallone F, MacDonald TT. TGF-beta1 and Smad7 in the regulation of IBD. Mucosal Immunol. 2008;1(Suppl 1):S50–3. doi: 10.1038/mi.2008.55.PubMedCrossRefGoogle Scholar
  55. 55.
    Schiavi E, Smolinska S, O’Mahony L. Intestinal dendritic cells. Curr Opin Gastroenterol. 2015;31:98–103. doi: 10.1097/MOG.0000000000000155.PubMedCrossRefGoogle Scholar
  56. 56.
    del Rio ML, Bernhardt G, Rodriguez-Barbosa JI, Forster R. Development and functional specialization of CD103+ dendritic cells. Immunol Rev. 2010;234:268–81. doi: 10.1111/j.0105-2896.2009.00874.x.PubMedCrossRefGoogle Scholar
  57. 57.
    Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563–604. doi: 10.1146/annurev-immunol-020711-074950.PubMedCrossRefGoogle Scholar
  58. 58.
    Muzaki AR, Tetlak P, Sheng J, Loh SC, Setiagani YA, Poidinger M, Zolezzi F, Karjalainen K, Ruedl C. Intestinal CD103CD11b dendritic cells restrain colitis via IFN-gamma-induced anti-inflammatory response in epithelial cells. Mucosal Immunol. 2016;9(2):336–51. doi: 10.1038/mi.2015.64.PubMedCrossRefGoogle Scholar
  59. 59.
    Watchmaker PB, Lahl K, Lee M, Baumjohann D, Morton J, Kim SJ, Zeng R, Dent A, Ansel KM, Diamond B, Hadeiba H, Butcher EC. Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol. 2014;15:98–108. doi: 10.1038/ni.2768.PubMedCrossRefGoogle Scholar
  60. 60.
    Stock A, Napolitani G, Cerundolo V. Intestinal DC in migrational imprinting of immune cells. Immunol Cell Biol. 2013;91:240–9. doi: 10.1038/icb.2012.73.PubMedCrossRefGoogle Scholar
  61. 61.
    Qualls JE, Tuna H, Kaplan AM, Cohen DA. Suppression of experimental colitis in mice by CD11c+ dendritic cells. Inflamm Bowel Dis. 2009;15:236–47. doi: 10.1002/ibd.20733.PubMedCrossRefGoogle Scholar
  62. 62.
    Ermann J, Staton T, Glickman JN, de Waal MR, Glimcher LH. 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 U S A. 2014;111:E2559–66. doi: 10.1073/pnas.1408540111.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt LF, Bluestone JA, Sheppard D. Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature. 2007;449:361–5. doi: nature06110 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Hart AL, Al-Hassi HO, Rigby RJ, Bell SJ, Emmanuel AV, Knight SC, Kamm MA, Stagg AJ. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology. 2005;129:50–65.PubMedCrossRefGoogle Scholar
  65. 65.
    Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med. 2015;21:698–708. doi: 10.1038/nm.3892.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Yokoyama WM, Kim S, French AR. The dynamic life of natural killer cells. Annu Rev Immunol. 2004;22:405–29. doi: 10.1146/annurev.immunol.22.012703.104711.PubMedCrossRefGoogle Scholar
  67. 67.
    Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol. 2004;5:1260–5. doi: ni1138 [pii]PubMedCrossRefGoogle Scholar
  68. 68.
    Steel AW, Mela CM, Lindsay JO, Gazzard BG, Goodier MR. Increased proportion of CD16(+) NK cells in the colonic lamina propria of inflammatory bowel disease patients, but not after azathioprine treatment. Aliment Pharmacol Ther. 2011;33:115–26. doi: 10.1111/j.1365-2036.2010.04499.x.PubMedCrossRefGoogle Scholar
  69. 69.
    Hanash AM, Dudakov JA, Hua G, O’Connor MH, Young LF, Singer NV, West ML, Jenq RR, Holland AM, Kappel LW, Ghosh A, Tsai JJ, Rao UK, Yim NL, Smith OM, Velardi E, Hawryluk EB, Murphy GF, Liu C, Fouser LA, Kolesnick R, Blazar BR, van den Brink MR. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 2012;37:339–50. doi: 10.1016/j.immuni.2012.05.028.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Mielke LA, Jones SA, Raverdeau M, Higgs R, Stefanska A, Groom JR, Misiak A, Dungan LS, Sutton CE, Streubel G, Bracken AP, Mills KH. Retinoic acid expression associates with enhanced IL-22 production by gamma delta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med. 2013;210:1117–24. doi: 10.1084/jem.20121588.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Berard M, Kleinschek M, Cua D, Di Santo JP, Eberl G. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol. 2011;12:320–6. doi: 10.1038/ni.2002.PubMedCrossRefGoogle Scholar
  72. 72.
    Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118:534–44. doi: 10.1172/JCI33194.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, Hreggvidsdottir HS, Heinsbroek SE, Legrand N, Buskens CJ, Bemelman WA, Mjosberg JM, Spits H. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013;14:221–9. doi: 10.1038/ni.2534.PubMedCrossRefGoogle Scholar
  74. 74.
    Ciccia F, Accardo-Palumbo A, Alessandro R, Rizzo A, Principe S, Peralta S, Raiata F, Giardina A, De Leo G, Triolo G. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012;64:1869–78. doi: 10.1002/art.34355.PubMedCrossRefGoogle Scholar
  75. 75.
    Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, Cella M, Colonna M. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. 2013;38:769–81. doi: 10.1016/j.immuni.2013.02.010.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J, Matuzaki Y, Suzuki S, Sugita A, Koganei K, Hisamatsu T, Kanai T, Hibi T. Imbalance of NKp44(+)NKp46(−) and NKp44(−)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn’s disease. Gastroenterology. 2010;139:882–92, 892.e1–3. doi: 10.1053/j.gastro.2010.05.040.PubMedCrossRefGoogle Scholar
  77. 77.
    Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM, Dubrot J, Withers DR, Hugues S, Farrar MA, Reith W, Eberl G, Baldassano RN, Laufer TM, Elson CO, Sonnenberg GF. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4(+) T cells. Science. 2015;348:1031–5. doi: 10.1126/science.aaa4812.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010;464:1371–5. doi: 10.1038/nature08949.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Munoz M, Eidenschenk C, Ota N, Wong K, Lohmann U, Kuhl AA, Wang X, Manzanillo P, Li Y, Rutz S, Zheng Y, Diehl L, Kayagaki N, van Lookeren-Campagne M, Liesenfeld O, Heimesaat M, Ouyang W. Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity. 2015;42:321–31. doi: 10.1016/j.immuni.2015.01.011.PubMedCrossRefGoogle Scholar
  80. 80.
    Powell N, Walker AW, Stolarczyk E, Canavan JB, Gokmen MR, Marks E, Jackson I, Hashim A, Curtis MA, Jenner RG, Howard JK, Parkhill J, MacDonald TT, Lord GM. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity. 2012;37:674–84. doi: 10.1016/j.immuni.2012.09.008.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ, Travis SP, Powrie F. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 2011;208:1127–33. doi: 10.1084/jem.20101712.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Longman RS, Diehl GE, Victorio DA, Huh JR, Galan C, Miraldi ER, Swaminath A, Bonneau R, Scherl EJ, Littman DR. CX(3)CR1(+) mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med. 2014;211:1571–83. doi: 10.1084/jem.20140678.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Powell N, Lo JW, Biancheri P, Vossenkamper A, Pantazi E, Walker AW, Stolarczyk E, Ammoscato F, Goldberg R, Scott P, Canavan JB, Perucha E, Garrido-Mesa N, Irving PM, Sanderson JD, Hayee B, Howard JK, Parkhill J, MacDonald TT, Lord GM. Interleukin 6 increases production of cytokines by colonic innate lymphoid cells in mice and patients with chronic intestinal inflammation. Gastroenterology. 2015;149:456–67.e15. doi: 10.1053/j.gastro.2015.04.017.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Klose CS, Kiss EA, Schwierzeck V, Ebert K, Hoyler T, d’Hargues Y, Goppert N, Croxford AL, Waisman A, Tanriver Y, Diefenbach A. A T-bet gradient controls the fate and function of CCR6-RORgammat+ innate lymphoid cells. Nature. 2013;494:261–5. doi: 10.1038/nature11813.PubMedCrossRefGoogle Scholar
  85. 85.
    Vonarbourg C, Mortha A, Bui VL, Hernandez PP, Kiss EA, Hoyler T, Flach M, Bengsch B, Thimme R, Holscher C, Honig M, Pannicke U, Schwarz K, Ware CF, Finke D, Diefenbach A. Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity. 2010;33:736–51. doi: 10.1016/j.immuni.2010.10.017.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Kanamori Y, Ishimaru K, Nanno M, Maki K, Ikuta K, Nariuchi H, Ishikawa H. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J Exp Med. 1996;184:1449–59.PubMedCrossRefGoogle Scholar
  87. 87.
    Groh V, Steinle A, Bauer S, Spies T. Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science. 1998;279:1737–40.PubMedCrossRefGoogle Scholar
  88. 88.
    Ferreira LM. Gammadelta T cells: innately adaptive immune cells? Int Rev Immunol. 2013;32:223–48. doi: 10.3109/08830185.2013.783831.PubMedCrossRefGoogle Scholar
  89. 89.
    Fukushima K, Masuda T, Ohtani H, Sasaki I, Funayama Y, Matsuno S, Nagura H. Immunohistochemical characterization, distribution, and ultrastructure of lymphocytes bearing T-cell receptor gamma/delta in inflammatory bowel disease. Gastroenterology. 1991;101:670–8. doi: S0016508591003104 [pii]PubMedCrossRefGoogle Scholar
  90. 90.
    McVay LD, Li B, Biancaniello R, Creighton MA, Bachwich D, Lichtenstein G, Rombeau JL, Carding SR. Changes in human mucosal gamma delta T cell repertoire and function associated with the disease process in inflammatory bowel disease. Mol Med. 1997;3:183–203.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A. 2002;99:14338–43. doi: 10.1073/pnas.212290499.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Hoffmann JC, Peters K, Henschke S, Herrmann B, Pfister K, Westermann J, Zeitz M. Role of T lymphocytes in rat 2,4,6-trinitrobenzene sulphonic acid (TNBS) induced colitis: increased mortality after gammadelta T cell depletion and no effect of alpha beta T cell depletion. Gut. 2001;48:489–95.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Inagaki-Ohara K, Chinen T, Matsuzaki G, Sasaki A, Sakamoto Y, Hiromatsu K, Nakamura-Uchiyama F, Nawa Y, Yoshimura A. Mucosal T cells bearing TCR gamma delta play a protective role in intestinal inflammation. J Immunol. 2004;173:1390–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Tsuchiya T, Fukuda S, Hamada H, Nakamura A, Kohama Y, Ishikawa H, Tsujikawa K, Yamamoto H. Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol. 2003;171:5507–13.PubMedCrossRefGoogle Scholar
  95. 95.
    Kawaguchi-Miyashita M, Shimada S, Kurosu H, Kato-Nagaoka N, Matsuoka Y, Ohwaki M, Ishikawa H, Nanno M. An accessory role of TCR gamma delta (+) cells in the exacerbation of inflammatory bowel disease in TCR alpha mutant mice. Eur J Immunol. 2001;31:980–8. doi:10.1002/1521-4141(200104)31:4<980:AID-IMMU980>3.0.CO;2-U. [pii]Google Scholar
  96. 96.
    Simpson SJ, Hollander GA, Mizoguchi E, Allen D, Bhan AK, Wang B, Terhorst C. Expression of pro-inflammatory cytokines by TCR alpha beta+ and TCR gamma delta+ T cells in an experimental model of colitis. Eur J Immunol. 1997;27:17–25. doi: 10.1002/eji.1830270104.PubMedCrossRefGoogle Scholar
  97. 97.
    Shimamoto M, Ueno Y, Tanaka S, Onitake T, Hanaoka R, Yoshioka K, Hatakeyama T, Chayama K. Selective decrease in colonic CD56(+) T and CD161(+) T cells in the inflamed mucosa of patients with ulcerative colitis. World J Gastroenterol. 2007;13:5995–6002.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113:1490–7. doi: 10.1172/JCI19836.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Vossenkamper A, Blair PA, Safinia N, Fraser LD, Das L, Sanders TJ, Stagg AJ, Sanderson JD, Taylor K, Chang F, Choong LM, D’Cruz DP, Macdonald TT, Lombardi G, Spencer J. A role for gut-associated lymphoid tissue in shaping the human B cell repertoire. J Exp Med. 2013;210:1665–74. doi: 10.1084/jem.20122465.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Melchers F. Checkpoints that control B cell development. J Clin Invest. 2015;125:2203–10. doi: 10.1172/JCI78083.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131:959–71. doi: 10.1016/j.jaci.2013.01.046.PubMedCrossRefGoogle Scholar
  102. 102.
    Brandtzaeg P, Prydz H. Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulins. Nature. 1984;311:71–3.PubMedCrossRefGoogle Scholar
  103. 103.
    Macpherson AJ, Koller Y, McCoy KD. The bilateral responsiveness between intestinal microbes and IgA. Trends Immunol. 2015;36:460–70. doi: 10.1016/ Scholar
  104. 104.
    Benveniste J, Lespinats G, Adam C, Salomon JC. Immunoglobulins in intact, immunized, and contaminated axenic mice: study of serum IgA. J Immunol. 1971;107:1647–55.PubMedGoogle Scholar
  105. 105.
    Benveniste J, Lespinats G, Salomon J. Serum and secretory IgA in axenic and holoxenic mice. J Immunol. 1971;107:1656–62.PubMedGoogle Scholar
  106. 106.
    Dominguez O, Giner MT, Alsina L, Martin MA, Lozano J, Plaza AM. Clinical phenotypes associated with selective IgA deficiency: a review of 330 cases and a proposed follow-up protocol. An Pediatr (Barc). 2012;76:261–7. doi: 10.1016/j.anpedi.2011.11.006.CrossRefGoogle Scholar
  107. 107.
    Ludvigsson JF, Neovius M, Hammarstrom L. Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study. J Clin Immunol. 2014;34:444–51. doi: 10.1007/s10875-014-0009-4.PubMedCrossRefGoogle Scholar
  108. 108.
    Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev. 2014;13:163–77. doi: 10.1016/j.autrev.2013.10.005.PubMedCrossRefGoogle Scholar
  109. 109.
    Konrad A, Cong Y, Duck W, Borlaza R, Elson CO. Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology. 2006;130:2050–9. doi: 10.1053/j.gastro.2006.02.055.PubMedCrossRefGoogle Scholar
  110. 110.
    Macpherson AJ, Uhr T. Compartmentalization of the mucosal immune responses to commensal intestinal bacteria. Ann N Y Acad Sci. 2004;1029:36–43. doi: 10.1196/annals.1309.005.PubMedCrossRefGoogle Scholar
  111. 111.
    Dubinsky MC, Lin YC, Dutridge D, Picornell Y, Landers CJ, Farrior S, Wrobel I, Quiros A, Vasiliauskas EA, Grill B, Israel D, Bahar R, Christie D, Wahbeh G, Silber G, Dallazadeh S, Shah P, Thomas D, Kelts D, Hershberg RM, Elson CO, Targan SR, Taylor KD, Rotter JI, Yang H, Western Regional Pediatric IBD Research Alliance. Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am J Gastroenterol. 2006;101:360–7. doi: AJG456 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Spencer J, Dillon SB, Isaacson PG, MacDonald TT. T cell subclasses in fetal human ileum. Clin Exp Immunol. 1986;65:553–8.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Spencer J, MacDonald TT, Isaacson PG. Heterogeneity of non-lymphoid cells expressing HLA-D region antigens in human fetal gut. Clin Exp Immunol. 1987;67:415–24.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Cornes JS. Peyer’s patches in the human gut. Proc R Soc Med. 1965;58:716.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Castellino F, Germain RN. Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu Rev Immunol. 2006;24:519–40. doi: 10.1146/annurev.immunol.23.021704.115825.PubMedCrossRefGoogle Scholar
  116. 116.
    Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A. 1998;95:258–63.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89. doi: 10.1146/annurev-immunol-030409-101212.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature. 2003;424:88–93. doi: 10.1038/nature01726.PubMedCrossRefGoogle Scholar
  119. 119.
    Kugathasan S, Saubermann LJ, Smith L, Kou D, Itoh J, Binion DG, Levine AD, Blumberg RS, Fiocchi C. Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut. 2007;56:1696–705. doi: gut.2006.116467 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Hovhannisyan Z, Treatman J, Littman DR, Mayer L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology. 2011;140:957–65. doi: 10.1053/j.gastro.2010.12.002.PubMedCrossRefGoogle Scholar
  121. 121.
    Pariente B, Mocan I, Camus M, Dutertre CA, Ettersperger J, Cattan P, Gornet JM, Dulphy N, Charron D, Lemann M, Toubert A, Allez M. Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn’s disease. Gastroenterology. 2011;141:217–26, 226.e1–2. doi: 10.1053/j.gastro.2011.03.061.PubMedCrossRefGoogle Scholar
  122. 122.
    Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L, Villanova F, Tosi I, Capon F, Trembath RC, Peris K, Nestle FO. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS One. 2011;6:e17160. doi: 10.1371/journal.pone.0017160.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Cong Y, Brandwein SL, McCabe RP, Lazenby A, Birkenmeier EH, Sundberg JP, Elson CO. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med. 1998;187:855–64.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Probert CS, Chott A, Turner JR, Saubermann LJ, Stevens AC, Bodinaku K, Elson CO, Balk SP, Blumberg RS. Persistent clonal expansions of peripheral blood CD4+ lymphocytes in chronic inflammatory bowel disease. J Immunol. 1996;157:3183–91.PubMedGoogle Scholar
  125. 125.
    Furfaro F, Fiorino G, Allocca M, Gilardi D, Danese S. Emerging therapeutic targets and strategies in Crohn’s disease. Expert Rev Gastroenterol Hepatol. 2016;10(6):735–44. doi: 10.1586/17474124.2016.1142372.PubMedCrossRefGoogle Scholar
  126. 126.
    Feuerer M, Hill JA, Mathis D, Benoist C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol. 2009;10:689–95. doi: 10.1038/ni.1760.PubMedCrossRefGoogle Scholar
  127. 127.
    van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007;2007:89017. doi: 10.1155/2007/89017.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Lochner M, Wang Z, Sparwasser T. The special relationship in the development and function of T helper 17 and regulatory T cells. Prog Mol Biol Transl Sci. 2015;136:99–129. doi: 10.1016/bs.pmbts.2015.07.013.PubMedCrossRefGoogle Scholar
  129. 129.
    Huber S, Gagliani N, Esplugues E, O’Connor Jr W, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34:554–65. doi: 10.1016/j.immuni.2011.01.020.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Boden EK, Snapper SB. Regulatory T cells in inflammatory bowel disease. Curr Opin Gastroenterol. 2008;24:733–41.PubMedCrossRefGoogle Scholar
  131. 131.
    Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol. 2015;21:11236–45. doi: 10.3748/wjg.v21.i40.11236.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, Nakamura T, Koganei K, Fukushima T, Watanabe M. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol. 2004;173:3119–30.Google Scholar
  133. 133.
    Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, Duchmann R. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128:1868–78. doi: S0016508505005664 [pii]PubMedCrossRefGoogle Scholar
  134. 134.
    Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology. 2004;127:224–38. doi: S001650850​4007103 [pii]Google Scholar
  135. 135.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–41. doi: 10.1016/j.cell.2004.07.002.PubMedCrossRefGoogle Scholar
  136. 136.
    Gutierrez-Martinez E, Planes R, Anselmi G, Reynolds M, Menezes S, Adiko AC, Saveanu L, Guermonprez P. Cross-presentation of cell-associated antigens by MHC class I in dendritic cell subsets. Front Immunol. 2015;6:363. doi: 10.3389/fimmu.2015.00363.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Voedisch S, Koenecke C, David S, Herbrand H, Forster R, Rhen M, Pabst O. Mesenteric lymph nodes confine dendritic cell-mediated dissemination of Salmonella enterica serovar Typhimurium and limit systemic disease in mice. Infect Immun. 2009;77:3170–80. doi: 10.1128/IAI.00272-09.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci U S A. 2000;97:6043–8. doi: 97/11/6043 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr. 1999;69:1035S–45S.PubMedGoogle Scholar
  140. 140.
    Mellander L, Carlsson B, Jalil F, Soderstrom T, Hanson LA. Secretory IgA antibody response against Escherichia coli antigens in infants in relation to exposure. J Pediatr. 1985;107:430–3.PubMedCrossRefGoogle Scholar
  141. 141.
    Fadel S, Sarzotti M. Cellular immune responses in neonates. Int Rev Immunol. 2000;19:173–93.PubMedCrossRefGoogle Scholar
  142. 142.
    Hassiotou F, Geddes DT. Immune cell-mediated protection of the mammary gland and the infant during breastfeeding. Adv Nutr. 2015;6:267–75. doi: 10.3945/an.114.007377.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Adderson EE. Antibody repertoires in infants and adults: effects of T-independent and T-dependent immunizations. Springer Semin Immunopathol. 2001;23:387–403.PubMedCrossRefGoogle Scholar
  144. 144.
    Hill DA, Grundmeier RW, Ram G, Spergel JM. The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study. BMC Pediatr. 2016;16:133.doi: 10.1186/s12887-016-0673-z.
  145. 145.
    Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med. 2004;199:1679–88. doi: 10.1084/jem.20032121.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Namork E, Stensby BA. Peanut sensitization pattern in Norwegian children and adults with specific IgE to peanut show age related differences. Allergy Asthma Clin Immunol. 2015;11:32-015-0095-8. doi: 10.1186/s13223-015-0095-8.eCollection 2015CrossRefGoogle Scholar
  147. 147.
    Turfkruyer M, Rekima A, Macchiaverni P, Le Bourhis L, Muncan V, van den Brink GR, Tulic MK, Verhasselt V. Oral tolerance is inefficient in neonatal mice due to a physiological vitamin A deficiency. Mucosal Immunol. 2016;9(2):479–91. doi: 10.1038/mi.2015.114.PubMedCrossRefGoogle Scholar
  148. 148.
    Bamias G, Martin C, Mishina M, Ross WG, Rivera-Nieves J, Marini M, Cominelli F. Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology. 2005;128:654–66. doi: S0016508504021584 [pii]PubMedCrossRefGoogle Scholar
  149. 149.
    Spencer DM, Veldman GM, Banerjee S, Willis J, Levine AD. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology. 2002;122:94–105. doi: S0016508502653715 [pii]PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Allergy and ImmunologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Department of Gastroenterology and HepatologyMayo ClinicRochesterUSA

Personalised recommendations