The Mucosal Adjuvant Cholera Toxin B Instructs Non-Mucosal Dendritic Cells to Promote IgA Production Via Retinoic Acid and TGF-[beta]

• Published in: PloS one 2013-03, Vol.8 (3), p.e59822
• Main Authors: Gloudemans, Anouk K, Plantinga, Maud, Guilliams, Martin, Willart, Monique A, Ozir-Fazalalikhan, Arifa, van der Ham, Alwin, Boon, Louis, Harris, Nicola L, Hammad, Hamida, Hoogsteden, Henk C, Yazdanbakhsh, Maria, Hendriks, Rudi W, Lambrecht, Bart N, Smits, Hermelijn H
• Format: Article
• Language: English
• Subjects: Analysis; Care and treatment; Cholera toxin; Dendritic cells; Immunoglobulin A; Risk factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0059822

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-[beta] 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-[beta] signaling inhibitor or neutralizing anti-TGF-[beta] was added, demonstrating the involvement of RA and TGF-[beta] 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.