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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 cells.

Journal article
Authors Jia-Bin Sun
Sukanya Raghavan
Åsa Sjöling
Samuel B Lundin
Jan Holmgren
Published in Journal of immunology (Baltimore, Md. : 1950)
Volume 177
Issue 11
Pages 7634-44
ISSN 0022-1767
Publication year 2006
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 7634-44
Language en
Links www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Administration, Oral, Adoptive Transfer, Animals, Cell Proliferation, Cholera Toxin, administration & dosage, immunology, Female, Flow Cytometry, Forkhead Transcription Factors, immunology, metabolism, Immune Tolerance, Interleukin-2, biosynthesis, Interleukin-2 Receptor alpha Subunit, immunology, metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Ovalbumin, administration & dosage, immunology, T-Lymphocytes, Regulatory, immunology
Subject categories Medical and Health Sciences

Abstract

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-beta in serum. This could be abolished by co-administering cholera toxin or by treatment with anti-TGF-beta 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-beta 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).

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