Oral Tolerance in the Absence of Naturally Occurring Tregs

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2005 Jun 7

PMID 15937545

Citations 225

Authors

Daniel Mucida

Nino Kutchukhidze

Agustin Erazo

Momtchilo Russo

Juan J Lafaille

Maria A Curotto de Lafaille

Affiliations

Soon will be listed here.

Abstract

Mucosal tolerance prevents pathological reactions against environmental and food antigens, and its failure results in exacerbated inflammation typical of allergies and asthma. One of the proposed mechanisms of oral tolerance is the induction of Tregs. Using a mouse model of hyper-IgE and asthma, we found that oral tolerance could be effectively induced in the absence of naturally occurring thymus-derived Tregs. Oral antigen administration prior to i.p. immunization prevented effector/memory Th2 cell development, germinal center formation, class switching to IgE, and lung inflammation. Oral exposure to antigen induced development of antigen-specific CD4CD25Foxp3CD45RB cells that were anergic and displayed suppressive activity in vivo and in vitro. Oral tolerance to the Th2 allergic response was in large part dependent on TGF-beta and independent of IL-10. Interestingly, Tregs were also induced by single i.p. immunization with antigen and adjuvant. However, unlike oral administration of antigen, which induced Tregs but not effector T cells, i.p. immunization led to the simultaneous induction of Tregs and effector Th2 cells displaying the same antigen specificity.

Citing Articles

The renaissance of oral tolerance: merging tradition and new insights.

Cerovic V, Pabst O, Mowat A Nat Rev Immunol. 2024; 25(1):42-56.

PMID: 39242920 DOI: 10.1038/s41577-024-01077-7.

Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation.

Blanco T, Nakagawa H, Musayeva A, Krauthammer M, Singh R, Narimatsu A JCI Insight. 2024; 9(20).

PMID: 39235864 PMC: 11530131. DOI: 10.1172/jci.insight.182469.

Prdm16-dependent antigen-presenting cells induce tolerance to intestinal antigens.

Fu L, Upadhyay R, Pokrovskii M, Chen F, Romero-Meza G, Griesemer A bioRxiv. 2024; .

PMID: 39091750 PMC: 11291166. DOI: 10.1101/2024.07.23.604803.

Oral tolerance to dietary antigens and Foxp3 regulatory T cells.

Miranda-Waldetario M, Curotto de Lafaille M Immunol Rev. 2024; 326(1):8-16.

PMID: 39054615 PMC: 11436310. DOI: 10.1111/imr.13370.

Discovery and characterization of dietary antigens in oral tolerance.

Blum J, Kong R, Schulman E, Chen F, Upadhyay R, Romero-Meza G bioRxiv. 2024; .

PMID: 38853977 PMC: 11160622. DOI: 10.1101/2024.05.26.593976.

References

COHN L, Tepper J, Bottomly K . IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J Immunol. 1998; 161(8):3813-6. View

Fontenot J, Gavin M, Rudensky A . Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003; 4(4):330-6. DOI: 10.1038/ni904. View

Antov A, Yang L, Vig M, Baltimore D, Van Parijs L . Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol. 2003; 171(7):3435-41. DOI: 10.4049/jimmunol.171.7.3435. View

Read S, Malmstrom V, Powrie F . Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000; 192(2):295-302. PMC: 2193261. DOI: 10.1084/jem.192.2.295. View

Mowat A . Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003; 3(4):331-41. DOI: 10.1038/nri1057. View

Chen C, Lee W, Yun P, Snow P, Liu C . Induction of autoantigen-specific Th2 and Tr1 regulatory T cells and modulation of autoimmune diabetes. J Immunol. 2003; 171(2):733-44. DOI: 10.4049/jimmunol.171.2.733. View

Richman L, Chiller J, Brown W, Hanson D, Vaz N . Enterically induced immunologic tolerance. I. Induction of suppressor T lymphoyctes by intragastric administration of soluble proteins. J Immunol. 1978; 121(6):2429-34. View

Hauet-Broere F, Unger W, Garssen J, Hoijer M, Kraal G, Samsom J . Functional CD25- and CD25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application. Eur J Immunol. 2003; 33(10):2801-10. DOI: 10.1002/eji.200324115. View

Russo M, Nahori M, Lefort J, Gomes E, de Castro Keller A, Rodriguez D . Suppression of asthma-like responses in different mouse strains by oral tolerance. Am J Respir Cell Mol Biol. 2001; 24(5):518-26. DOI: 10.1165/ajrcmb.24.5.4320. View

10.

Rizzo L, Morawetz R, Choi R, Wiggert B, Chan C, Morse 3rd H . IL-4 and IL-10 are both required for the induction of oral tolerance. J Immunol. 1999; 162(5):2613-22. View

11.

Park H, Paik D, Jang E, Hong S, Youn J . Acquisition of anergic and suppressive activities in transforming growth factor-beta-costimulated CD4+CD25- T cells. Int Immunol. 2004; 16(8):1203-13. DOI: 10.1093/intimm/dxh123. View

12.

Fantini M, Becker C, Monteleone G, Pallone F, Galle P, Neurath M . Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172(9):5149-53. DOI: 10.4049/jimmunol.172.9.5149. View

13.

Khattri R, Cox T, Yasayko S, Ramsdell F . An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003; 4(4):337-42. DOI: 10.1038/ni909. View

14.

Apostolou I, von Boehmer H . In vivo instruction of suppressor commitment in naive T cells. J Exp Med. 2004; 199(10):1401-8. PMC: 2211808. DOI: 10.1084/jem.20040249. View

15.

Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo V, Weiner H . Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. 1995; 376(6536):177-80. DOI: 10.1038/376177a0. View

16.

Faria A, Weiner H . Oral tolerance: mechanisms and therapeutic applications. Adv Immunol. 1999; 73:153-264. DOI: 10.1016/s0065-2776(08)60787-7. View

17.

Stock P, Akbari O, Berry G, Freeman G, DeKruyff R, Umetsu D . Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol. 2004; 5(11):1149-56. DOI: 10.1038/ni1122. View

18.

Sundstedt A, ONeill E, Nicolson K, Wraith D . Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003; 170(3):1240-8. DOI: 10.4049/jimmunol.170.3.1240. View

19.

Cobbold S, Castejon R, Adams E, Zelenika D, Graca L, Humm S . Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol. 2004; 172(10):6003-10. DOI: 10.4049/jimmunol.172.10.6003. View

20.

Thorstenson K, Khoruts A . Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol. 2001; 167(1):188-95. DOI: 10.4049/jimmunol.167.1.188. View