Abstract
Intranasal chitosan-formulated DNA vaccination promotes IgA secretion in the intestine. However, the mechanism whereby chitosan-DNA skews IgA class switch recombination (CSR) of B cells in the Gut-associated lymph tissue (GALT) is not fully resolved. In this study, we investigated the effects of nasally administered chitosan-DNA (pcDNA3.1-VP1 plasmid encoding VP1 capsid protein of Coxsackievirus B3) on IgA production, DC activation and Tfh/Th17 response in the intestine. Compared to DNA immunization, intranasal chitosan-DNA vaccination induced antigen-specific IgA production in feces, a pronounced switching of antigen-specific IgA+ plasmablast B cells in the mesenteric lymph nodes (MLNs) and an enhanced expression of post-recombination Iα-CH transcripts/IgA germline transcript (αGT) as well as activation-induced cytidine deaminase (AID) in MLN B cells. MLN Tfh frequency was markedly enhanced by chitosan-DNA, and was associated with VP1-specific IgA titer. 24 h after immunization, intranasal chitosan-DNA induced a recruitment of CD103+DCs into the MLN that paralleled a selective loss of CD103+DCs in the lamina propria (LP). In vivo activated MLN-derived CD103+DCs produced high levels of IL-6 and BAFF in response to chitosan-DNA, which up-regulated transmembrane activator and CAML interactor (TACI) expression on MLN B cells. Upon co-culture with IgM+B in the presence of chitosan-DNA, MLN CD103+DCs induced IgA production in a T-dependent manner; and this IgA-promoting effect of CD103+DC was blocked by targeting TACI and, to a lower extent, by blocking IL-6. MLN CD103+DCs displayed an enhanced capacity to induce an enhanced CD4+Th17 response in vivo and in vitro, and IL-17A deficient mice had a pronounced reduction of specific intestinal IgA following immunization. Taken together, mesenteric CD103+DCs are indispensable for the adjuvant activity of chitosan in enhancing DNA vaccine-specific IgA switching in gut through activating BAFF-TACI and IL-6-IL-6R signaling, and through inducing Th17/Tfh differentiation in the MLN.
Highlights
The predominant immunoglobulin at the mucosal surfaces is secretory IgA (SIgA) serving as the first defense against pathogens through immune exclusion
We show that i.n. immunization with chitosan-DNA induces an enhanced recruitment of CD103+DCs into the Mesenteric lymph node (MLN), which markedly increases the differentiation of germinal centers (GC) T follicular helper (Tfh) cells, Agspecific IgA+ plasmablast and plasma cells
Viral protein 1 (VP1)-specific Ab-forming cells (AFCs) were weakly induced in the spleens and Peyer‘s patch (PP) and were not different among various vaccine groups; marked IgA responses (235 and 320 AFCs/106 cells) were observed in the MLNs and lamina propria (LP) of chitosanDNA-immunized mice that were significantly higher than those induced by DNA (105 and 265 AFCs/106 cells, Figure 1C)
Summary
The predominant immunoglobulin at the mucosal surfaces is secretory IgA (SIgA) serving as the first defense against pathogens through immune exclusion It plays important roles in establishing a healthy microbiota and maintaining mucosal homeostasis [1, 2]. An insufficient induction of effector T cells and SIgA in the lung at the time of Mycobacterium tuberculosis (M.tb) infection is suggested as one of the limitations of BCG vaccine [7] In this regard, mucosal immunization with vaccine antigens, or mucosal passive application of pathogen-specific SIgAs at the mucosa where is the initial entry site for most infectious agents, can be effective alternatives to achieve mucosal protection against severe mucus-related infectious disease [8]
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