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* University of Gothenburg Vaccine Research Institute and Department of Microbiology and Immunology, Institute of Biomedicine Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden;
International Vaccine Institute, Seoul, South Korea; and
Institut National de la Santé et de la Recherche Médicale, Unit 721, University of Nice, Sophia Antipolis, France
Mucosal administration of Ag conjugated to cholera toxin B subunit (CTB) can efficiently induce peripheral immunologic tolerance, so-called oral tolerance, associated with development of Foxp3+CD25+CD4+ regulatory T (Treg) cells. Using an established sublingual tolerization regimen with Ag(OVA)/CTB conjugate, wherein CTB mediates Ag uptake and presentation by most B lymphocytes irrespective of their Ag specificity, we have assessed the importance of B cells for induction of Ag-specific Treg cells and oral tolerance. We found that Treg cells are reduced in µMT–/– B cell-deficient mice compared with wild-type (WT) mice. After sublingual Ag/CTB treatment, Treg cells increased much more in WT than in µMT–/– mice; however, adoptive transfer of B cells before treatment normalized Treg cell development and functional oral tolerance. B cells from OVA/CTB-treated mice expressed more IL-10 and less CD86 than control B cells. Adoptive transfer of these cells before parenteral immunization with OVA led to efficient suppression of proliferation and to induction of apoptotic depletion of Ag-specific CD25–CD4+ effector T cells associated with the expansion of Treg cells. However, also OVA/CTB-treated µMT–/– mice could suppress the immune response to parenteral immunization with OVA, which was associated with a strong increase in Foxp3–CD4+ T cells expressing LAP/TGF-β. Our results indicate that mucosal tolerance comprises at least two separate pathways: one being B cell dependent and associated with expansion of Treg cells and Treg-mediated suppression and depletion of effector T cells, and one being B cell independent and associated with development of Foxp3–LAP+TGF-β+ regulatory T cells.
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1 This work was financially supported by grants to J.H. from The Marianne and Marcus Wallenberg Foundation, the Swedish Science Council (Medicine) (Project K2000-06X-03382), the Sahlgrenska University Hospital, and The Swedish Foundation for Strategic Research support of the Mucosal Immunology and Vaccine Program at the University of Gothenburg. The International Vaccine Institute is supported in part by the governments of Sweden, the Republic of Korea, The Netherlands, and Kuwait.
2 Address correspondence and reprint requests to Dr. Jia-Bin Sun, University of Gothenburg Vaccine Research Institute, Box 435, 405 30, Göteborg, Sweden. E-mail address: jia-bin.sun{at}microbio.gu.se
3 Abbreviations used in this paper: Teff, effector T; Treg, CD4+CD25+Foxp3+ regulatory T; CMLN, cervicomandibular lymph node; CTB, cholera toxin B subunit; DC, dendritic cell; DLN, draining lymph node; DTH, delayed-type hypersensitivity; Foxp3, the forkhead-winged helix family transcription factor; LAP, latency-associated peptide; MLN, mesenteric lymph node; s.l., sublingual; WT, wild type; Tg, transgenic; PLN, popliteal lymph node; 7AAD, 7-aminoactinomycin D; mTGF-β, membrane-bound TGF-β.
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