Vaccination strategies to promote mucosal antibody responses

Abstract

There are great interest and demand for the development of vaccines to prevent and treat diverse microbial infections. Mucosal vaccines elicit immune protection by stimulating the production of antibodies at mucosal surfaces and systemic districts. Being positioned in close proximity to a large community of commensal microbes, the mucosal immune system deploys a heterogeneous population of cells and a complex regulatory network to maintain the balance between surveillance and tolerance. A successful mucosal vaccine relies on leveraging the functions of these immune cells and regulatory components. We review the important cellular interactions and molecular pathways underlying the induction and regulation of mucosal antibody responses and discuss their implications on mucosal vaccination.

Figure 1

Major Cellular Interactions and Regulatory Pathways Involved in IgA Responses to Intestinal Antigens M cells from PPs sample commensal and vaccine antigens from the intestinal lumen and deliver them to subepithelial DCs. Antigen sampling is also carried out by CX₃CR1⁺ DCs that project dendrites into the intestinal lumen across ECs. These cells release immunoregulatory (TSLP) and IgA-inducing (BAFF and APRIL) molecules upon sensing microbial signatures through TLRs and NLRs. TSLP stimulates the formation of tolerogenic DCs that suppress proinflammatory T_h1 responses and induce noninflammatory Treg and Th2 responses by releasing IL-6, IL-10, TGF-β1, and RA. Treg cells may further differentiate into T_FH cells, which together with Treg and perhaps Th2 cells stimulate IgA CSR and production by stimulating naive IgM⁺IgD⁺ B cells through CD40L, TGF-β1, IL-6, IL-10, and IL-21. In the presence of RA, IgA-expressing B cells emerging from mucosal germinal centers acquire expression of gut-homing receptors such as CCR9 and α₄β₇, which direct subsequent B cell migration to the intestinal LP through efferent lymphatics, regional mesenteric lymph nodes, and blood circulation. In the LP, IgA-expressing B cells differentiate into IgA-secreting plasma cells that secrete IgA dimers. Interaction of IgA dimers with the pIgR results into IgA transcytosis and formation of a secretory IgA (SIgA) complex that binds antigen in the intestinal lumen. The LP also contains IL-10-producing macrophages and BAFF-APRIL-nitric oxide-producing TipDCs whose development is promoted by microbial and epithelial factors such as TSLP. TipDCs and macrophages would enhance local IgA production by triggering CSR and stimulating plasma cell survival.

Figure 2

Parallel Regulatory Mechanisms for Induction of Mucosal Immunity and Tolerance Intestinal ECs release immune regulatory factors, such as TSLP, RA, and TGF-β1, upon sensing antigens from the lumen. These immune mediators condition DCs to generate CD103⁺ DCs and TipDCs. Such regulatory DCs produce more immune regulatory factors, such as TGF-β1, RA, IL-10, and IL-27, which reinforce mucosal homeostasis and tolerance by promoting the development of IgA responses and regulatory T cell responses, including Treg and Tr1 responses. Treg and Tr1 cells suppress mucosal and systemic responses by T_h1 cells, T_h17 cells, and CTLs. Such a situation may represent a challenge for mucosal vaccines aimed at eliciting mucosal and systemic T cell-mediated immunity.