title: The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β.
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.
authors.affiliation: Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Anouk K
authors.initials: AK
authors.lastname: Gloudemans
authors.forename: Maud
authors.initials: M
authors.lastname: Plantinga
authors.forename: Martin
authors.initials: M
authors.lastname: Guilliams
authors.forename: Monique A
authors.initials: MA
authors.lastname: Willart
authors.forename: Arifa
authors.initials: A
authors.lastname: Ozir-Fazalalikhan
authors.forename: Alwin
authors.initials: A
authors.lastname: van der Ham
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Harris
authors.forename: Hamida
authors.initials: H
authors.lastname: Hammad
authors.forename: Henk C
authors.initials: HC
authors.lastname: Hoogsteden
authors.forename: Maria
authors.initials: M
authors.lastname: Yazdanbakhsh
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Hermelijn H
authors.initials: HH
authors.lastname: Smits
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D018929:Cell Culture Techniques; D002772:Cholera Toxin / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007070:Immunoglobulin A / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D017931:DNA Primers; D007070:Immunoglobulin A; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D002772:Cholera Toxin