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Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3⁺CD25⁺ and Foxp3^–CD25^– CD4⁺ Regulatory T Cells¹

Department of Microbiology and Immunology, Institute of Biomedicine and Göteborg University Vaccine Research Institute, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

Oral administration of Ag coupled to cholera toxin B subunit (CTB) efficiently induces peripheral immunological tolerance. We investigated the extent to which this oral tolerance is mediated by CD25⁺CD4⁺ regulatory T cells (T_reg). We found that total T_reg, KJ1–26⁺ T_reg and CTLA-4⁺ T_reg were all increased in Peyer’s patches, mesenteric lymph nodes, and, to a lesser extent, in spleen of mice after intragastric administration of OVA/CTB conjugate, which also increased TGF- in serum. This could be abolished by coadministering cholera toxin or by treatment with anti-TGF- mAb. CD25⁺ T_reg, but also CD25^–CD4⁺ T cells from OVA/CTB-treated BALB/c or DO11.10 mice efficiently suppressed effector T cell proliferation and IL-2 production in vitro. Following adoptive transfer, both T cell populations also suppressed OVA-specific T cell and delayed-type hypersensitivity responses in vivo. Foxp3 was strongly expressed by CD25⁺ T_reg from OVA/CTB-treated mice, and treatment also markedly expanded CD25⁺Foxp3⁺ T_reg. Furthermore, in Rag1^–/– mice that had adoptively received highly purified Foxp3^–CD25^–CD4⁺ OT-II T cells OVA/CTB feeding efficiently induced CD25⁺ T_reg cells, which expressed Foxp3 more strongly than naturally developing T_reg and also had stronger ability to suppress effector OT-II T cell proliferation. A remaining CD25^– T cell population, which also became suppressive in response to OVA/CTB treatment, did not express Foxp3. Our results demonstrate that oral tolerance induced by CTB-conjugated Ag is associated with increase in TGF- and in both the frequency and suppressive capacity of Foxp3⁺ and CTLA-4⁺ CD25⁺ T_reg together with the generation of both Foxp3⁺ and Foxp3^–CD25^– CD4⁺ T_reg.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Swedish Science Council Medicine Project (K2000-06X-03382), by the Knut and Alice Wallenberg Foundation through its support of the Göteborg University Vaccine Research Institute, and by the Swedish Foundation for Strategic Research through the Mucosal Immunology and Vaccine Center at Göteborg University, and a LUA/ALF Project Grant from the Sahlgrenska University Hospital.

² Address correspondence and reprint requests to Dr. Jia-Bin Sun, Department of Microbiology and Immunology, Institute of Biomedicine, Göteborg University, 405 30 Göteborg, Sweden. E-mail address: jia-bin.sun{at}microbio.gu.se

³ Abbreviations used in this paper: T_reg, regulatory T cell; PP, Peyer’s patch; LN, lymph node; MLN, mesenteric LN; CT, cholera toxin; CTB, CT B subunit; i.g., intragastric; DLN, draining LN; DC, dendritic cell; Tg, transgenic; T_eff, Tg T effector cell; DTH, delayed-type hypersensitivity; FPLC, fast protein liquid chromatography; Hprt, hypoxanthine phosphoribosyltransferase; MNC, mononuclear cell; int, intermediate.

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