Advertisement

The Role of the Gut in Type 2 Immunity

  • Caspar OhnmachtEmail author
Chapter
  • 411 Downloads
Part of the Birkhäuser Advances in Infectious Diseases book series (BAID)

Abstract

Allergic and autoimmune disorders have been on the raise in the last decades in westernized countries while infectious diseases could be dramatically reduced due to efficient vaccination campaigns, improvement of personal hygiene and use of medication. Alteration of immunological tolerance may be implicated in both autoimmune and allergic inflammation yet underlying mechanisms remain poorly understood. Microbes colonizing all barrier sites are now known to have strong impact on our general immune status. The intestinal tract harbors the densest community of microbes and in combination with a huge surface area, the microenvironment in the gut implies strong tolerogenic properties. While a healthy symbiosis between intestinal microbes and the immune system is beneficial for the host, dysbiosis of microbial communities can heavily impact on immune responses and immunological tolerance. A systemic effect on the general susceptibility to allergic and autoimmune disorders is difficult to study and remains controversial. As an alternative explanation, allergic sensibilisation via the skin or lung is thought to be an important pathway but lacks the capability to explain the increase of allergic disorders on an epidemiological level. In this chapter, I will highlight a possible impact of a beneficial host-microbiota relationship in both the intestinal tract and other mucosal surfaces.

References

  1. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455.  https://doi.org/10.1038/nature12726 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Arrieta MC, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, Kuzeljevic B, Gold MJ, Britton HM, Lefebvre DL, Subbarao P, Mandhane P, Becker A, McNagny KM, Sears MR, Kollmann T, Investigators CS, Mohn WW, Turvey SE, Brett Finlay B (2015) Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med 7(307):307ra152.  https://doi.org/10.1126/scitranslmed.aab2271 CrossRefPubMedGoogle Scholar
  3. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341.  https://doi.org/10.1126/science.1198469 CrossRefPubMedGoogle Scholar
  4. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500(7461):232–236.  https://doi.org/10.1038/nature12331 CrossRefPubMedGoogle Scholar
  5. Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, Ishikawa E, Shima T, Hara T, Kado S, Jinnohara T, Ohno H, Kondo T, Toyooka K, Watanabe E, Yokoyama S, Tokoro S, Mori H, Noguchi Y, Morita H, Ivanov II, Sugiyama T, Nunez G, Camp JG, Hattori M, Umesaki Y, Honda K (2015) Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163(2):367–380.  https://doi.org/10.1016/j.cell.2015.08.058 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A (2016) Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell 167(4):1067–1078.e1016.  https://doi.org/10.1016/j.cell.2016.09.050
  7. Barlow JL, Peel S, Fox J, Panova V, Hardman CS, Camelo A, Bucks C, Wu X, Kane CM, Neill DR, Flynn RJ, Sayers I, Hall IP, McKenzie AN (2013) IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J Allergy Clin Immunol 132(4):933–941.  https://doi.org/10.1016/j.jaci.2013.05.012 CrossRefPubMedGoogle Scholar
  8. Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H (2012) IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol 188(3):1503–1513.  https://doi.org/10.4049/jimmunol.1102832 CrossRefPubMedGoogle Scholar
  9. Barthels C, Ogrinc A, Steyer V, Meier S, Simon F, Wimmer M, Blutke A, Straub T, Zimber-Strobl U, Lutgens E, Marconi P, Ohnmacht C, Garzetti D, Stecher B, Brocker T (2017) CD40-signalling abrogates induction of RORgammat+ Treg cells by intestinal CD103+ DCs and causes fatal colitis. Nat Commun 8:14715.  https://doi.org/10.1038/ncomms14715 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Boirivant M, Fuss IJ, Chu A, Strober W (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188(10):1929–1939CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bruchard M, Rebe C, Derangere V, Togbe D, Ryffel B, Boidot R, Humblin E, Hamman A, Chalmin F, Berger H, Chevriaux A, Limagne E, Apetoh L, Vegran F, Ghiringhelli F (2015) The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat Immunol 16(8):859–870.  https://doi.org/10.1038/ni.3202 CrossRefPubMedGoogle Scholar
  12. Cahenzli J, Koller Y, Wyss M, Geuking MB, McCoy KD (2013) Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14(5):559–570.  https://doi.org/10.1016/j.chom.2013.10.004 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chen CC, Kobayashi T, Iijima K, Hsu FC, Kita H (2017) IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs. J Allergy Clin Immunol.  https://doi.org/10.1016/j.jaci.2017.01.015
  14. Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY (2016) An essential role for the IL-2 receptor in Treg cell function. Nat Immunol 17(11):1322–1333.  https://doi.org/10.1038/ni.3540 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA (2008) Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 358(11):1109–1117.  https://doi.org/10.1056/NEJMoa074943 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, Woodfolk JA, Platts-Mills TA (2009) Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol 123(2):426–433.  https://doi.org/10.1016/j.jaci.2008.10.052 CrossRefPubMedGoogle Scholar
  17. Commins SP, James HR, Kelly LA, Pochan SL, Workman LJ, Perzanowski MS, Kocan KM, Fahy JV, Nganga LW, Ronmark E, Cooper PJ, Platts-Mills TA (2011) The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose. J Allergy Clin Immunol 127(5):1286–1293.e1286.  https://doi.org/10.1016/j.jaci.2011.02.019
  18. Curotto de Lafaille MA, Kutchukhidze N, Shen S, Ding Y, Yee H, Lafaille JJ (2008) Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29(1):114–126.  https://doi.org/10.1016/j.immuni.2008.05.010 CrossRefPubMedGoogle Scholar
  19. Darrasse-Jeze G, Deroubaix S, Mouquet H, Victora GD, Eisenreich T, Yao KH, Masilamani RF, Dustin ML, Rudensky A, Liu K, Nussenzweig MC (2009) Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med 206(9):1853–1862.  https://doi.org/10.1084/jem.20090746 CrossRefPubMedPubMedCentralGoogle Scholar
  20. de Kleer IM, Kool M, de Bruijn MJ, Willart M, van Moorleghem J, Schuijs MJ, Plantinga M, Beyaert R, Hams E, Fallon PG, Hammad H, Hendriks RW, Lambrecht BN (2016) Perinatal activation of the interleukin-33 pathway promotes type 2 immunity in the developing lung. Immunity 45(6):1285–1298.  https://doi.org/10.1016/j.immuni.2016.10.031 CrossRefPubMedGoogle Scholar
  21. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, Brough HA, Phippard D, Basting M, Feeney M, Turcanu V, Sever ML, Gomez Lorenzo M, Plaut M, Lack G, LEAP Study Team (2015) Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 372(9):803–813.  https://doi.org/10.1056/NEJMoa1414850 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, Kay AB, Hamid QA (1996) Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. J Allergy Clin Immunol 97(6):1356–1365CrossRefPubMedGoogle Scholar
  23. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrlander C, Heederik D, Piarroux R, von Mutius E, GABRIELA Transregio 22 Study Group (2011) Exposure to environmental microorganisms and childhood asthma. N Engl J Med 364(8):701–709.  https://doi.org/10.1056/NEJMoa1007302 CrossRefPubMedGoogle Scholar
  24. Esterhazy D, Loschko J, London M, Jove V, Oliveira TY, Mucida D (2016) Classical dendritic cells are required for dietary antigen-mediated induction of peripheral T(reg) cells and tolerance. Nat Immunol 17(5):545–555.  https://doi.org/10.1038/ni.3408 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6(11):1142–1151.  https://doi.org/10.1038/ni1263 CrossRefPubMedGoogle Scholar
  26. Fujimura KE, Sitarik AR, Havstad S, Lin DL, Levan S, Fadrosh D, Panzer AR, LaMere B, Rackaityte E, Lukacs NW, Wegienka G, Boushey HA, Ownby DR, Zoratti EM, Levin AM, Johnson CC, Lynch SV (2016) Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med 22(10):1187–1191.  https://doi.org/10.1038/nm.4176 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450.  https://doi.org/10.1038/nature12721 CrossRefPubMedGoogle Scholar
  28. Galand C, Leyva-Castillo JM, Yoon J, Han A, Lee MS, McKenzie AN, Stassen M, Oyoshi MK, Finkelman FD, Geha RS (2016) IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells. J Allergy Clin Immunol 138(5):1356–1366.  https://doi.org/10.1016/j.jaci.2016.03.056 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gao Y, Nish SA, Jiang R, Hou L, Licona-Limon P, Weinstein JS, Zhao H, Medzhitov R (2013) Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39(4):722–732.  https://doi.org/10.1016/j.immuni.2013.08.028 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Gause WC, Wynn TA, Allen JE (2013) Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol 13(8):607–614.  https://doi.org/10.1038/nri3476 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, McCoy KD, Macpherson AJ (2011) Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34(5):794–806.  https://doi.org/10.1016/j.immuni.2011.03.021 CrossRefPubMedGoogle Scholar
  32. Geva-Zatorsky N, Sefik E, Kua L, Pasman L, Tan TG, Ortiz-Lopez A, Yanortsang TB, Yang L, Jupp R, Mathis D, Benoist C, Kasper DL (2017) Mining the human gut microbiota for immunomodulatory organisms. Cell 168(5):928–943.e911.  https://doi.org/10.1016/j.cell.2017.01.022
  33. Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, Nicod LP, Lloyd CM, Marsland BJ (2014) Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med.  https://doi.org/10.1038/nm.3568
  34. Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, Pachynski R, Nguyen L, Ghodsi A, Adler S, Butcher EC (2012) Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36(3):438–450.  https://doi.org/10.1016/j.immuni.2012.01.017 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hammad H, Plantinga M, Deswarte K, Pouliot P, Willart MA, Kool M, Muskens F, Lambrecht BN (2010) Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 207(10):2097–2111.  https://doi.org/10.1084/jem.20101563 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Han D, Walsh MC, Cejas PJ, Dang NN, Kim YF, Kim J, Charrier-Hisamuddin L, Chau L, Zhang Q, Bittinger K, Bushman FD, Turka LA, Shen H, Reizis B, Defranco AL, Wu GD, Choi Y (2013) Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity 38(6):1211–1222.  https://doi.org/10.1016/j.immuni.2013.05.012 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Herbst T, Sichelstiel A, Schar C, Yadava K, Burki K, Cahenzli J, McCoy K, Marsland BJ, Harris NL (2011) Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med 184(2):198–205.  https://doi.org/10.1164/rccm.201010-1574OC CrossRefPubMedGoogle Scholar
  38. Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, Kambayashi T, Larosa DF, Renner ED, Orange JS, Bushman FD, Artis D (2012) Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 18(4):538–546.  https://doi.org/10.1038/nm.2657 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133.  https://doi.org/10.1016/j.cell.2006.07.035 CrossRefPubMedGoogle Scholar
  40. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139(3):485–498.  https://doi.org/10.1016/j.cell.2009.09.033 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Josefowicz SZ, Lu LF, Rudensky AY (2012a) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564.  https://doi.org/10.1146/annurev.immunol.25.022106.141623 CrossRefPubMedGoogle Scholar
  42. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY (2012b) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482(7385):395–399.  https://doi.org/10.1038/nature10772 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Julia V, Macia L, Dombrowicz D (2015) The impact of diet on asthma and allergic diseases. Nat Rev Immunol 15(5):308–322.  https://doi.org/10.1038/nri3830 CrossRefPubMedGoogle Scholar
  44. Kabat AM, Harrison OJ, Riffelmacher T, Moghaddam AE, Pearson CF, Laing A, Abeler-Dorner L, Forman SP, Grencis RK, Sattentau Q, Simon AK, Pott J, Maloy KJ (2016) The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. elife 5:e12444.  https://doi.org/10.7554/eLife.12444 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Kashiwagi M, Hosoi J, Lai JF, Brissette J, Ziegler SF, Morgan BA, Georgopoulos K (2017) Direct control of regulatory T cells by keratinocytes. Nat Immunol 18(3):334–343.  https://doi.org/10.1038/ni.3661 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Kawamoto S, Maruya M, Kato LM, Suda W, Atarashi K, Doi Y, Tsutsui Y, Qin H, Honda K, Okada T, Hattori M, Fagarasan S (2014) Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41(1):152–165.  https://doi.org/10.1016/j.immuni.2014.05.016 CrossRefPubMedGoogle Scholar
  47. Kim KS, Hong SW, Han D, Yi J, Jung J, Yang BG, Lee JY, Lee M, Surh CD (2016) Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351(6275):858–863.  https://doi.org/10.1126/science.aac5560 CrossRefPubMedGoogle Scholar
  48. Kluger MA, Luig M, Wegscheid C, Goerke B, Paust HJ, Brix SR, Yan I, Mittrucker HW, Hagl B, Renner ED, Tiegs G, Wiech T, Stahl RA, Panzer U, Steinmetz OM (2014) Stat3 programs Th17-specific regulatory T cells to control GN. J Am Soc Nephrol 25(6):1291–1302.  https://doi.org/10.1681/ASN.2013080904 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kluger MA, Nosko A, Ramcke T, Goerke B, Meyer MC, Wegscheid C, Luig M, Tiegs G, Stahl RA, Steinmetz OM (2017) RORgammat expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses. Clin Exp Immunol 188(1):63–78.  https://doi.org/10.1111/cei.12905 CrossRefPubMedGoogle Scholar
  50. Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE, Iwasaki A (2013) CD301b(+) dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39(4):733–743.  https://doi.org/10.1016/j.immuni.2013.08.029 CrossRefPubMedGoogle Scholar
  51. Lange-Asschenfeldt B, Marenbach D, Lang C, Patzelt A, Ulrich M, Maltusch A, Terhorst D, Stockfleth E, Sterry W, Lademann J (2011) Distribution of bacteria in the epidermal layers and hair follicles of the human skin. Skin Pharmacol Physiol 24(6):305–311.  https://doi.org/10.1159/000328728 CrossRefPubMedGoogle Scholar
  52. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh CS (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478(7368):250–254.  https://doi.org/10.1038/nature10434 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Legoux FP, Lim JB, Cauley AW, Dikiy S, Ertelt J, Mariani TJ, Sparwasser T, Way SS, Moon JJ (2015) CD4(+) T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43(5):896–908.  https://doi.org/10.1016/j.immuni.2015.10.011 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Levine AG, Arvey A, Jin W, Rudensky AY (2014) Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 15(11):1070–1078.  https://doi.org/10.1038/ni.3004 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Levine AG, Hemmers S, Baptista AP, Schizas M, Faire MB, Moltedo B, Konopacki C, Schmidt-Supprian M, Germain RN, Treuting PM, Rudensky AY (2017) Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity. J Exp Med 214(3):609–622.  https://doi.org/10.1084/jem.20161318 PubMedPubMedCentralGoogle Scholar
  56. Lexmond WS, Goettel JA, Lyons JJ, Jacobse J, Deken MM, Lawrence MG, DiMaggio TH, Kotlarz D, Garabedian E, Sackstein P, Nelson CC, Jones N, Stone KD, Candotti F, Rings EH, Thrasher AJ, Milner JD, Snapper SB, Fiebiger E (2016) FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J Clin Invest 126(10):4030–4044.  https://doi.org/10.1172/JCI85129 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J, Martin MG, Chatila TA (2005) Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 116(5):1106–1115.  https://doi.org/10.1016/j.jaci.2005.08.046 CrossRefPubMedGoogle Scholar
  58. Lochner M, Berard M, Sawa S, Hauer S, Gaboriau-Routhiau V, Fernandez TD, Snel J, Bousso P, Cerf-Bensussan N, Eberl G (2011) Restricted microbiota and absence of cognate TCR antigen leads to an unbalanced generation of Th17 cells. J Immunol 186(3):1531–1537.  https://doi.org/10.4049/jimmunol.1001723 CrossRefPubMedGoogle Scholar
  59. Lodge CJ, Tan DJ, Lau MX, Dai X, Tham R, Lowe AJ, Bowatte G, Allen KJ, Dharmage SC (2015) Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr 104(467):38–53.  https://doi.org/10.1111/apa.13132 CrossRefPubMedGoogle Scholar
  60. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R (2012) Diversity, stability and resilience of the human gut microbiota. Nature 489(7415):220–230.  https://doi.org/10.1038/nature11550 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Mantel PY, Kuipers H, Boyman O, Rhyner C, Ouaked N, Ruckert B, Karagiannidis C, Lambrecht BN, Hendriks RW, Crameri R, Akdis CA, Blaser K, Schmidt-Weber CB (2007) GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 5(12):e329.  https://doi.org/10.1371/journal.pbio.0050329 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Massoud AH, Charbonnier LM, Lopez D, Pellegrini M, Phipatanakul W, Chatila TA (2016) An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 22(9):1013–1022.  https://doi.org/10.1038/nm.4147 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Metz M, Piliponsky AM, Chen CC, Lammel V, Abrink M, Pejler G, Tsai M, Galli SJ (2006) Mast cells can enhance resistance to snake and honeybee venoms. Science 313(5786):526–530.  https://doi.org/10.1126/science.1128877 CrossRefPubMedGoogle Scholar
  64. Morton AM, Sefik E, Upadhyay R, Weissleder R, Benoist C, Mathis D (2014) Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut. Proc Natl Acad Sci USA 111(18):6696–6701.  https://doi.org/10.1073/pnas.1405634111 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115(7):1923–1933.  https://doi.org/10.1172/JCI24487 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Noti M, Wojno ED, Kim BS, Siracusa MC, Giacomin PR, Nair MG, Benitez AJ, Ruymann KR, Muir AB, Hill DA, Chikwava KR, Moghaddam AE, Sattentau QJ, Alex A, Zhou C, Yearley JH, Menard-Katcher P, Kubo M, Obata-Ninomiya K, Karasuyama H, Comeau MR, Brown-Whitehorn T, de Waal Malefyt R, Sleiman PM, Hakonarson H, Cianferoni A, Falk GW, Wang ML, Spergel JM, Artis D (2013) Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat Med 19(8):1005–1013.  https://doi.org/10.1038/nm.3281 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, Sattentau QA, Comeau MR, Spergel JM, Artis D (2014) Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 133(5):1390–1399, 1399.e1391–1396.  https://doi.org/10.1016/j.jaci.2014.01.021
  68. Noval Rivas M, Burton OT, Wise P, Charbonnier LM, Georgiev P, Oettgen HC, Rachid R, Chatila TA (2015) Regulatory T cell reprogramming toward a Th2-Cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42(3):512–523.  https://doi.org/10.1016/j.immuni.2015.02.004 CrossRefPubMedGoogle Scholar
  69. Ohnmacht C (2016) Tolerance to the Intestinal Microbiota Mediated by ROR(gammat)(+) Cells. Trends Immunol 37(7):477–486.  https://doi.org/10.1016/j.it.2016.05.002 CrossRefPubMedGoogle Scholar
  70. Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, Busslinger M, Cerf-Bensussan N, Boneca IG, Voehringer D, Hase K, Honda K, Sakaguchi S, Eberl G (2015) MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science 349(6251):989–993.  https://doi.org/10.1126/science.aac4263 CrossRefPubMedGoogle Scholar
  71. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, Blumberg RS (2012) Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336(6080):489–493.  https://doi.org/10.1126/science.1219328 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Ozcan E, Notarangelo LD, Geha RS (2008) Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol 122(6):1054–1062.  https://doi.org/10.1016/j.jaci.2008.10.023 CrossRefPubMedGoogle Scholar
  73. Plantinga M, Guilliams M, Vanheerswynghels M, Deswarte K, Branco-Madeira F, Toussaint W, Vanhoutte L, Neyt K, Killeen N, Malissen B, Hammad H, Lambrecht BN (2013) Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38(2):322–335.  https://doi.org/10.1016/j.immuni.2012.10.016 CrossRefPubMedGoogle Scholar
  74. Platzer B, Baker K, Vera MP, Singer K, Panduro M, Lexmond WS, Turner D, Vargas SO, Kinet JP, Maurer D, Baron RM, Blumberg RS, Fiebiger E (2015) Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites. Mucosal Immunol 8(3):516–532.  https://doi.org/10.1038/mi.2014.85 PubMedGoogle Scholar
  75. Round JL, Mazmanian SK (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 107(27):12204–12209.  https://doi.org/10.1073/pnas.0909122107 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, Gill N, Blanchet MR, Mohn WW, McNagny KM, Finlay BB (2012) Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep 13(5):440–447.  https://doi.org/10.1038/embor.2012.32 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Russell SL, Gold MJ, Reynolds LA, Willing BP, Dimitriu P, Thorson L, Redpath SA, Perona-Wright G, Blanchet MR, Mohn WW, Finlay BB, McNagny KM (2015) Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases. J Allergy Clin Immunol 135(1):100–109.  https://doi.org/10.1016/j.jaci.2014.06.027 CrossRefPubMedGoogle Scholar
  78. Sanchez Rodriguez R, Pauli ML, Neuhaus IM, Yu SS, Arron ST, Harris HW, Yang SH, Anthony BA, Sverdrup FM, Krow-Lucal E, Mackenzie TC, Johnson DS, Meyer EH, Lohr A, Hsu A, Koo J, Liao W, Gupta R, Debbaneh MG, Butler D, Huynh M, Levin EC, Leon A, Hoffman WY, McGrath MH, Alvarado MD, Ludwig CH, Truong HA, Maurano MM, Gratz IK, Abbas AK, Rosenblum MD (2014) Memory regulatory T cells reside in human skin. J Clin Invest 124(3):1027–1036.  https://doi.org/10.1172/jci72932 CrossRefPubMedPubMedCentralGoogle Scholar
  79. Scharschmidt TC, Vasquez KS, Truong HA, Gearty SV, Pauli ML, Nosbaum A, Gratz IK, Otto M, Moon JJ, Liese J, Abbas AK, Fischbach MA, Rosenblum MD (2015) A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43(5):1011–1021.  https://doi.org/10.1016/j.immuni.2015.10.016 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Scharschmidt TC, Vasquez KS, Pauli ML, Leitner EG, Chu K, Truong HA, Lowe MM, Sanchez Rodriguez R, Ali N, Laszik ZG, Sonnenburg JL, Millar SE, Rosenblum MD (2017) Commensal microbes and hair follicles morphogenesis coordinately drive treg migration into neonatal skin. Cell Host Microbe 21(4):467–477.e5.  https://doi.org/10.1016/j.chom.2017.03.001
  81. Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BM, Lohning M, Belkaid Y, Fallon PG, Powrie F (2014) The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature.  https://doi.org/10.1038/nature13577
  82. Schuijs MJ, Willart MA, Vergote K, Gras D, Deswarte K, Ege MJ, Madeira FB, Beyaert R, van Loo G, Bracher F, von Mutius E, Chanez P, Lambrecht BN, Hammad H (2015) Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349(6252):1106–1110.  https://doi.org/10.1126/science.aac6623 CrossRefPubMedGoogle Scholar
  83. Secrist H, Chelen CJ, Wen Y, Marshall JD, Umetsu DT (1993) Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J Exp Med 178(6):2123–2130CrossRefPubMedGoogle Scholar
  84. Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C (2015) MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 349(6251):993–997.  https://doi.org/10.1126/science.aaa9420 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Siede J, Frohlich A, Datsi A, Hegazy AN, Varga DV, Holecska V, Saito H, Nakae S, Lohning M (2016) IL-33 receptor-expressing regulatory T cells are highly activated, Th2 biased and suppress CD4 T cell proliferation through IL-10 and TGFbeta release. PLoS One 11(8):e0161507.  https://doi.org/10.1371/journal.pone.0161507 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Singh N, Thangaraju M, Prasad PD, Martin PM, Lambert NA, Boettger T, Offermanns S, Ganapathy V (2010) Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J Biol Chem 285(36):27601–27608.  https://doi.org/10.1074/jbc.M110.102947 CrossRefPubMedPubMedCentralGoogle Scholar
  87. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS (1998) Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 101(8):1614–1622.  https://doi.org/10.1172/JCI1647 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Stefka AT, Feehley T, Tripathi P, Qiu J, McCoy K, Mazmanian SK, Tjota MY, Seo GY, Cao S, Theriault BR, Antonopoulos DA, Zhou L, Chang EB, Fu YX, Nagler CR (2014) Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci USA 111(36):13145–13150.  https://doi.org/10.1073/pnas.1412008111 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Stein MM, Hrusch CL, Gozdz J, Igartua C, Pivniouk V, Murray SE, Ledford JG, Marques dos Santos M, Anderson RL, Metwali N, Neilson JW, Maier RM, Gilbert JA, Holbreich M, Thorne PS, Martinez FD, von Mutius E, Vercelli D, Ober C, Sperling AI (2016) Innate immunity and asthma risk in amish and hutterite farm children. N Engl J Med 375(5):411–421.  https://doi.org/10.1056/NEJMoa1508749 CrossRefPubMedPubMedCentralGoogle Scholar
  90. Sujino T, London M, Hoytema van Konijnenburg DP, Rendon T, Buch T, Silva HM, Lafaille JJ, Reis BS, Mucida D (2016) Tissue adaptation of regulatory and intraepithelial CD4(+) T cells controls gut inflammation. Science 352(6293):1581–1586.  https://doi.org/10.1126/science.aaf3892 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Tanoue T, Atarashi K, Honda K (2016) Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 16(5):295–309.  https://doi.org/10.1038/nri.2016.36 CrossRefPubMedGoogle Scholar
  92. Tordesillas L, Goswami R, Benede S, Grishina G, Dunkin D, Jarvinen KM, Maleki SJ, Sampson HA, Berin MC (2014) Skin exposure promotes a Th2-dependent sensitization to peanut allergens. J Clin Invest 124(11):4965–4975.  https://doi.org/10.1172/JCI75660 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, Marsland BJ (2014) Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20(2):159–166.  https://doi.org/10.1038/nm.3444 CrossRefPubMedGoogle Scholar
  94. Tsai M, Starkl P, Marichal T, Galli SJ (2015) Testing the ‘toxin hypothesis of allergy’: mast cells, IgE, and innate and acquired immune responses to venoms. Curr Opin Immunol 36:80–87.  https://doi.org/10.1016/j.coi.2015.07.001 CrossRefPubMedPubMedCentralGoogle Scholar
  95. Tussiwand R, Everts B, Grajales-Reyes GE, Kretzer NM, Iwata A, Bagaitkar J, Wu X, Wong R, Anderson DA, Murphy TL, Pearce EJ, Murphy KM (2015) Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 42(5):916–928.  https://doi.org/10.1016/j.immuni.2015.04.017 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Ubeda C, Pamer EG (2012) Antibiotics, microbiota, and immune defense. Trends Immunol 33(9):459–466.  https://doi.org/10.1016/j.it.2012.05.003 CrossRefPubMedPubMedCentralGoogle Scholar
  97. Ulges A, Klein M, Reuter S, Gerlitzki B, Hoffmann M, Grebe N, Staudt V, Stergiou N, Bohn T, Bruhl TJ, Muth S, Yurugi H, Rajalingam K, Bellinghausen I, Tuettenberg A, Hahn S, Reissig S, Haben I, Zipp F, Waisman A, Probst HC, Beilhack A, Buchou T, Filhol-Cochet O, Boldyreff B, Breloer M, Jonuleit H, Schild H, Schmitt E, Bopp T (2015) Protein kinase CK2 enables regulatory T cells to suppress excessive T2 responses in vivo. Nat Immunol.  https://doi.org/10.1038/ni.3083
  98. Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, Riess D, Hein MY, Buch T, Polic B, Schonle A, Zeiser R, Schmitt-Graff A, Kretschmer K, Klein L, Korn T, Sakaguchi S, Schmidt-Supprian M (2014) Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41(5):722–736.  https://doi.org/10.1016/j.immuni.2014.10.012 CrossRefPubMedGoogle Scholar
  99. Varney VA, Hamid QA, Gaga M, Ying S, Jacobson M, Frew AJ, Kay AB, Durham SR (1993) Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest 92(2):644–651.  https://doi.org/10.1172/JCI116633 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Vatanen T, Kostic AD, d’Hennezel E, Siljander H, Franzosa EA, Yassour M, Kolde R, Vlamakis H, Arthur TD, Hamalainen AM, Peet A, Tillmann V, Uibo R, Mokurov S, Dorshakova N, Ilonen J, Virtanen SM, Szabo SJ, Porter JA, Lahdesmaki H, Huttenhower C, Gevers D, Cullen TW, Knip M, DIABIMMUNE Study Group, Xavier RJ (2016) Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165(4):842–853.  https://doi.org/10.1016/j.cell.2016.04.007 CrossRefPubMedPubMedCentralGoogle Scholar
  101. Verhasselt V, Milcent V, Cazareth J, Kanda A, Fleury S, Dombrowicz D, Glaichenhaus N, Julia V (2008) Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 14(2):170–175.  https://doi.org/10.1038/nm1718 CrossRefPubMedGoogle Scholar
  102. Wang Y, Su MA, Wan YY (2011) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35(3):337–348.  https://doi.org/10.1016/j.immuni.2011.08.012 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Williams JW, Tjota MY, Clay BS, Vander Lugt B, Bandukwala HS, Hrusch CL, Decker DC, Blaine KM, Fixsen BR, Singh H, Sciammas R, Sperling AI (2013) Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat Commun 4(2990).  https://doi.org/10.1038/ncomms3990
  104. Wilson MS, Taylor MD, Balic A, Finney CA, Lamb JR, Maizels RM (2005) Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 202(9):1199–1212.  https://doi.org/10.1084/jem.20042572 CrossRefPubMedPubMedCentralGoogle Scholar
  105. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275.  https://doi.org/10.1126/science.1160062 CrossRefPubMedGoogle Scholar
  106. Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R, Paul WE, Bosselut R, Wei G, Zhao K, Oukka M, Zhu J, Belkaid Y (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 121(11):4503–4515.  https://doi.org/10.1172/JCI57456 CrossRefPubMedPubMedCentralGoogle Scholar
  107. Wu C, Chen Z, Dardalhon V, Xiao S, Thalhamer T, Liao M, Madi A, Franca RF, Han T, Oukka M, Kuchroo V (2017) The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat Immunol 18(3):344–353.  https://doi.org/10.1038/ni.3667 CrossRefPubMedPubMedCentralGoogle Scholar
  108. Yang BH, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M, Fohse L, Prinz I, Pezoldt J, Suerbaum S, Sparwasser T, Hamann A, Floess S, Huehn J, Lochner M (2016) Foxp3(+) T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9(2):444–457.  https://doi.org/10.1038/mi.2015.74 CrossRefPubMedGoogle Scholar
  109. Yu F, Sharma S, Edwards J, Feigenbaum L, Zhu J (2014) Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat Immunol.  https://doi.org/10.1038/ni.3053
  110. Zaiss MM, Rapin A, Lebon L, Dubey LK, Mosconi I, Sarter K, Piersigilli A, Menin L, Walker AW, Rougemont J, Paerewijck O, Geldhof P, McCoy KD, Macpherson AJ, Croese J, Giacomin PR, Loukas A, Junt T, Marsland BJ, Harris NL (2015) The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation. Immunity 43(5):998–1010.  https://doi.org/10.1016/j.immuni.2015.09.012 CrossRefPubMedPubMedCentralGoogle Scholar
  111. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236):351–356.  https://doi.org/10.1038/nature07674 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Center of Allergy and Environment (ZAUM)Technical University Munich and Helmholtz Zentrum MunichMunichGermany

Personalised recommendations