An Impressive Example of Peripheral Tolerance Against Nonself: Tolerance to Commensal Bacterial and Dietary Protein Antigens

  • Walter Gottlieb Land


This chapter deals with commensal bacteria and dietary proteins which can be regarded as typical examples of well-tolerated nonself. The specific unresponsiveness to commensal bacteria together with tolerance induction to dietary proteins is subsumed under the phenomenon of oral tolerance to nonself that can be regarded as an expression of peripheral tolerance. Several suppressive principles of the host have been identified to protect commensal microorganisms including interleukin-10, IgA antibodies, innate lymphocytes such as gammadelta T cells, and distinct gut-resident Foxp3+ regulatory T cells. Whereas peripheral regulatory T cells in other organs have T cell receptors specific for self antigens, intestinal regulatory T cells have a distinct set of T cell receptors that are specific for intestinal harmless microbial and dietary nonself antigens. The differentiation, migration, accumulation, and maintenance of intestinal regulatory T cells are promoted by both specialized intestinal dendritic cells and specific signals from the local environment, including individual members of the microbiota such as Clostridia species. It has been becoming increasingly apparent that the superstruction of intestinal tolerance to microbial antigens derived from commensals and dietary antigens derived from ingested food reflects considerable complexity. Understanding the development and the maintenance of intestinal regulatory T cells provides valuable insights into both intestinal homeostasis of the host and disease-relevant host-microbe interactions.


  1. 1.
    Tsuji NM, Kosaka A. Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells. Trends Immunol. 2008;29:532–40. Available from: CrossRefGoogle Scholar
  2. 2.
    Tanoue T, Atarashi K, Honda K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol. 2016;16:295–309. Available from: CrossRefGoogle Scholar
  3. 3.
    Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, Santacruz N, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478:250–4. Scholar
  4. 4.
    Nutsch KM, Hsieh C-ST. cell tolerance and immunity to commensal bacteria. Curr Opin Immunol. 2012;24:385–91. Available from: CrossRefGoogle Scholar
  5. 5.
    Omenetti S, Pizarro TT. The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front Immunol. 2015;6:639. Available from: CrossRefGoogle Scholar
  6. 6.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41. Scholar
  7. 7.
    Stefka AT, Feehley T, Tripathi P, Qiu J, McCoy K, Mazmanian SK, et al. Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci U S A. 2014;111:13145–50. Scholar
  8. 8.
    Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3 + T reg cells. J Exp Med. 2012;209:1723–42. Available from: CrossRefGoogle Scholar
  9. 9.
    Kawamoto S, Maruya M, Kato LM, Suda W, Atarashi K. Y, et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity. 2014;41:152–65. Available from: CrossRefGoogle Scholar
  10. 10.
    Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW, Ota M, et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science. 2013;340:1456–9. Scholar
  11. 11.
    Geuking MB, Cahenzli J, Lawson MAE, Ng DCK, Slack E, Hapfelmeier S, et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011;34:794–806. Available from: CrossRefGoogle Scholar
  12. 12.
    Kim KS, Hong S-W, Han D, Yi J, Jung J, Yang B-G, et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science. 2016;351:858–63. Scholar
  13. 13.
    Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013;497:258–62. Scholar
  14. 14.
    Farache J, Koren I, Milo I, Gurevich I, Kim K-W, Zigmond E, et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity. 2013;38:581–95. Available from: CrossRefGoogle Scholar
  15. 15.
    McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, Knoop KA, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature. 2012;483:345–9. Available from: CrossRefGoogle Scholar
  16. 16.
    Coombes JL, Siddiqui KRR, Arancibia-Cárcamo CV, Hall J, Sun C-M, Belkaid Y, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–64. Scholar
  17. 17.
    Bakdash G, Vogelpoel LTC, van Capel TMM, Kapsenberg ML, de Jong EC. Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells. Mucosal Immunol. 2015;8:265–78. Scholar
  18. 18.
    Pedros C, Duguet F, Saoudi A, Chabod M. Disrupted regulatory T cell homeostasis in inflammatory bowel diseases. World J Gastroenterol. 2016;22:974–95. Available from: CrossRefGoogle Scholar
  19. 19.
    Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500:232–6. Scholar
  20. 20.
    Sun C-M, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204:1775–85. Scholar
  21. 21.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–60. Scholar
  22. 22.
    DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011;471:220–4. Scholar
  23. 23.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8. Available from: CrossRefGoogle Scholar
  24. 24.
    Rezende RM, Weiner HL. History and mechanisms of oral tolerance. Semin Immunol. 2017;30:3–11. Available from: CrossRefGoogle Scholar
  25. 25.
    Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–95. Scholar
  26. 26.
    van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. Available from: CrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University of StrasbourgMolecular ImmunoRheumatology, Laboratory of Excellence TransplantexStrasbourgFrance

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