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.
Highlights
Secretory immunoglobulin A (SIgA) is abundantly present at mucosal surfaces of the gastrointestinal and respiratory tract
IgA induction by non-mucosal bone marrow derived (BM)-dendritic cells (DCs) was compared to bona fide mucosal PPDCs, representing the natural IgA inducing capacity of cells specialized in promoting this response
B cells exposed to Cholera Toxin subunit B (CTB) or LPS+CTB did not produce IgA, indicating that CTB did not act on B cells directly
Summary
Secretory immunoglobulin A (SIgA) is abundantly present at mucosal surfaces of the gastrointestinal and respiratory tract. SIgA, prevents pathogens and commensal bacteria from binding to epithelial cells, it prevents ingested or inhaled allergens to cause immunopathology and it neutralizes toxins, broadly acting to maintain homeostasis in the gut and lung [1,2,3,4]. TI IgA synthesis is induced in polyclonal naıve B cells by dendritic cell (DC)- and epithelial cell- derived molecules, such as proliferationinducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-b or nitric oxide (NO) [9,10,11]. Mucosal conditioning of DCs occurs via tissue-derived factors, such as RA and TGF-b, and by (commensal) bacteria expressing Toll-like receptor (TLR) ligands [13,14,15]
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