Abstract
It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-β or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-β signaling inhibitor or neutralizing anti-TGF-β was added, demonstrating the involvement of RA and TGF-β in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / pharmacology*
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Analysis of Variance
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Animals
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B-Lymphocytes / metabolism
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Cell Culture Techniques
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Cholera Toxin / pharmacology*
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DNA Primers / genetics
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Dendritic Cells / metabolism*
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Enzyme-Linked Immunosorbent Assay
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Female
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Immunoglobulin A / biosynthesis*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Myeloid Differentiation Factor 88 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Statistics, Nonparametric
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Transforming Growth Factor beta / metabolism*
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Tretinoin / metabolism*
Substances
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Adjuvants, Immunologic
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DNA Primers
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Immunoglobulin A
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Transforming Growth Factor beta
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Tretinoin
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Cholera Toxin
Grants and funding
This work was supported by the Dutch Organization for Scientific Research (NWO), Grant No ZONMW 40-40100-94-9024 (HHS), STW 10725 (YZ and HHS), the Netherlands Asthma Foundation (NAF) Grant No 06.043 (AKG). BNL is a recipient of an Odysseus Grant of the Fonds Wetenschappelijk Onderzoek (FWO) Flanders, a European Research Council (ERC) grant of the EU, and of a Multidisciplinary Research Partnerships (MRP) grant of Ghent University (Group-ID consortium). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.