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B lymphocytes treated in vitro with antigen coupled to cholera toxin B subunit induce antigen-specific Foxp3(+) regulatory T cells and protect against experimental autoimmune encephalomyelitis.

Journal article
Authors Jia-Bin Sun
Cecil Czerkinsky
Jan Holmgren
Published in Journal of immunology
Volume 188
Issue 4
Pages 1686-1697
ISSN 1550-6606
Publication year 2012
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 1686-1697
Language en
Links dx.doi.org/10.4049/jimmunol.1101771
Keywords Adoptive Transfer, methods, Animals, Antigens, immunology, B-Lymphocytes, drug effects, immunology, metabolism, CD4-Positive T-Lymphocytes, immunology, Cell Proliferation, drug effects, Cholera Toxin, administration & dosage, immunology, Encephalomyelitis, Autoimmune, Experimental, immunology, Female, Forkhead Transcription Factors, analysis, Glycoproteins, immunology, Immune Tolerance, Interferon-gamma, biosynthesis, Interleukin-17, biosynthesis, immunology, Lymphocyte Activation, immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Ovalbumin, immunology, pharmacology, Peptide Fragments, immunology, Recombinant Fusion Proteins, T-Lymphocytes, Regulatory, immunology, metabolism
Subject categories Basic Medicine, Immunology in the medical area

Abstract

The ability of activated B cells to protect against various experimental autoimmune or allergic diseases makes them attractive for use in cell-based therapies. We describe an efficient way to generate B cells with strong suppressive functions by incubating naive B cells with a relevant Ag conjugated to cholera toxin B subunit (CTB). This allows most B cells, irrespective of BCR, to take up and present Ag and induces their expression of latency-associated polypeptide (LAP)/TGF-β and after adoptive transfer also their production of IL-10. With OVA as model Ag, when naive T cells were cocultured in vitro with B cells pretreated with OVA conjugated to CTB (OVA/CTB) Ag-specific CD4(+) Foxp3 regulatory T (Treg) cells increased >50-fold. These cells effectively suppressed CD25(-)CD4(+) effector T (Teff) cells in secondary cultures. Adoptive transfer of OVA/CTB-treated B cells to mice subsequently immunized with OVA in CFA induced increase in Foxp3 Treg cells together with suppression and depletion of Teff cells. Likewise, adoptive transfer of B cells pulsed with myelin oligodendrocyte glycoprotein peptide(35-55) (MOGp) conjugated to CTB increased the number of Treg cells, suppressed MOGp-specific T cell proliferation and IL-17 and IFN-γ production, and prevented the development of experimental autoimmune encephalomyelitis. Similar effects were seen when B cells were given "therapeutically" to mice with early-stage experimental autoimmune encephalomyelitis. Our results suggest that B cells pulsed in vitro with relevant Ag/CTB conjugates may be used in cell therapy to induce Ag-specific suppression of autoimmune disease.

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