Mucosal Immune System and M Cell-targeting Strategies for Oral Mucosal Vaccination

Abstract

Vaccination is one of the most effective methods available to prevent infectious diseases. Mucosa, which are exposed to heavy loads of commensal and pathogenic microorganisms, are one of the first areas where infections are established, and therefore have frontline status in immunity, making mucosa ideal sites for vaccine application. Moreover, vaccination through the mucosal immune system could induce effective systemic immune responses together with mucosal immunity in contrast to parenteral vaccination, which is a poor inducer of effective immunity at mucosal surfaces. Among mucosal vaccines, oral mucosal vaccines have the advantages of ease and low cost of vaccine administration. The oral mucosal immune system, however, is generally recognized as poorly immunogenic due to the frequent induction of tolerance against orally-introduced antigens. Consequently, a prerequisite for successful mucosal vaccination is that the orally introduced antigen should be transported across the mucosal surface into the mucosa-associated lymphoid tissue (MALT). In particular, M cells are responsible for antigen uptake into MALT, and the rapid and effective transcytotic activity of M cells makes them an attractive target for mucosal vaccine delivery, although simple transport of the antigen into M cells does not guarantee the induction of specific immune responses. Consequently, development of mucosal vaccine adjuvants based on an understanding of the biology of M cells has attracted much research interest. Here, we review the characteristics of the oral mucosal immune system and delineate strategies to design effective oral mucosal vaccines with an emphasis on mucosal vaccine adjuvants.

Keywords: Adjuvant; Complement 5a receptor; Mucosal immune system; Vaccine.

Figure 1

Gut-associated mucosal immune system. In the intestinal immune system, Peyer's patches and isolated lymphoid follicles are inductive sties, while the lamina propria is the effector site. T cell-dependent activation of IgA⁺ B cells is induced in Peyer's patches. Dendritic cells located beneath the specialized M cells take up and process antigens, and naïve CD4+ T cells are primed. Follicular helper T cells expressing Bcl-6 and CXCR5 interact with B cells in the follicular dendritic cell network and aid in IgA isotype switching in the germinal center. IgA+ long-lived plasma cells and memory B cells migrate to effector sites in the lamina propria (9). SIgA plays critical roles in mucosal immune responses such as immune exclusion, antigen excretion, and intracellular virus neutralization.

Figure 2

The Co1 M cell-targeting ligand is able to induce antigen-specific immune responses after oral administration of ligand-conjugated antigen. We found that the M cell-targeting ligand Co1, which is selected by M-like cell-specific binding (A), is able to deliver conjugated antigen into mouse M cells and induce antigen-specific immune responses in systemic and mucosal compartments (B). A targeting receptor on M cells for the Co1 ligand was expected to be C5aR because the Co1 ligand has 60% amino acid sequence homology with OmpH α1 helix of Y. enterocolitica, which is similar in sequence to skp of E. coli, which is a ligand for C5aR. We verified that C5aR is expressed on both mouse M cells and human M-like cells and that it interacts with Y. enterocolitica (C).