Abstract
Native cholera toxin (nCT) as a nasal adjuvant was shown to elicit increased levels of T-independent S-IgA antibody (Ab) responses through IL-5- IL-5 receptor interactions between CD4+ T cells and IgA+ B-1 B cells in murine submandibular glands (SMGs) and nasal passages (NPs). Here, we further investigate whether oral-nasopharyngeal dendritic cells (DCs) play a central role in the induction of B-1 B cell IgA class switch recombination (CSR) for the enhancement of T cell-independent (TI) mucosal S-IgA Ab responses. High expression levels of activation-induced cytidine deaminase, Iα-Cμ circulation transcripts and Iμ-Cα transcripts were seen on B-1 B cells purified from SMGs and NPs of both TCRβ−/− mice and wild-type mice given nasal trinitrophenyl (TNP)-LPS plus nCT, than in the same tissues of mice given nCT or TNP-LPS alone. Further, DCs from SMGs, NPs and NALT of mice given nasal TNP-LPS plus nCT expressed significantly higher levels of a proliferation-inducing ligand (APRIL) than those in mice given TNP-LPS or nCT alone, whereas the B-1 B cells in SMGs and NPs showed elevated levels of transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI) expression. Interestingly, high frequencies of IgA+ B-1 B cells were induced when peritoneal IgA− IgM+ B cells were stimulated with mucosal DCs from mice given nasal TNP-LPS plus nCT. Taken together, these findings show that nasal nCT plays a key role in the enhancement of mucosal DC-mediated TI IgA CSR by B-1 B cells through their interactions with APRIL and TACI.
Highlights
Immunoglobulin A (IgA) antibody (Ab) is known as the most abundant Ig isotype in humans, and this isotype is induced by cellular and molecular mucosal interactions between IgA-committed B cells, helper CD4+ T cells, epithelial cells and their derived cytokines. [1,2] In order to induce efficient antigen (Ag)-specific IgA Ab responses, live attenuated viral or bacterial delivery systems or mucosal adjuvants are generally required
We have previously reported that native cholera toxin (nCT) can be used as an adjuvant to enhance the induction of T cell-independent (TI) Ag, i.e., TNP-LPS-specific mucosal SIgA Ab responses through an interaction between IL-5 receptorexpressing B-1 B cells and IL-5-producing CD4+ T cells in the submandibular glands (SMGs) and nasal passages (NPs) [34]
Since it has been reported that intestinal dendritic cells (DCs) induce TI IgA class switch recombination (CSR) through a proliferation inducing ligand (APRIL) and BAFF molecules [21], we examined whether nCT-activated DCs from SMGs and NPs express these molecules
Summary
Immunoglobulin A (IgA) antibody (Ab) is known as the most abundant Ig isotype in humans, and this isotype is induced by cellular and molecular mucosal interactions between IgA-committed B cells, helper CD4+ T cells, epithelial cells and their derived cytokines. [1,2] In order to induce efficient antigen (Ag)-specific IgA Ab responses, live attenuated viral or bacterial delivery systems or mucosal adjuvants are generally required. IgA-committed B cells migrate to diffuse mucosal effector tissues, including the nasal passages (NPs) and intestinal lamina propria (iLP), respectively [14,15] In addition to these mucosal inductive tissues, it is known that IgA CSR occurs in the absence of T cells in the iLP [16,17,18]. We hypothesized that IgA switching occurs in B-1 B cells in the SMGs and NPs via the Ig isotype switching-associated molecules produced by mucosal DCs. Here we focused on the cellular and molecular mechanisms for the induction of IgA CSR induced by nasal nCT as a mucosal adjuvant for immune responses to TI Ags
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