A novel M cell-based strategy to boost immune responses to oral vaccines: induction of intestinal villous M cells by RANKL pretreatment leads to enhanced vaccine uptake and improved antibody responses (144.26)

Abstract

Abstract An established strategy for improving immune responses to mucosal vaccines relies on targeting ligands to promote vaccine uptake by microfold (M) cells. M cells are antigen-sampling epithelial cells mostly found in the epithelium covering Peyer’s patches and other organized mucosal lymphoid tissues, but also present on a subset (~7%) of small intestinal villi as villous M cells (vM). Recently we showed that 4 days of systemic treatment (50 μg s.c. per day) with RANKL, a TNF superfamily cytokine, induces differentiation of vM on 100% of small intestinal villi, dramatically increasing the total number of available vM and leading to large increases in uptake of fluorescently labeled bacteria (30-fold) and 200 nm microspheres (100-fold). The present study was done to test a novel strategy for enhancing mucosal vaccine responses to oral vaccines based on RANKL pretreatment to induce supraphysiologic numbers of vM. Mice treated daily with RANKL beginning 4 days prior to a single oral immunization with 2 x 108 fixed OVA-expressing E. coli had an average 8-fold increase in the serum IgM anti-OVA response measured 7 to 11 days later. This effect of RANKL on the antibody response also synergized with the use of LPS as a systemic adjuvant given i.p. at the time of oral immunization. These results provide a proof of principle demonstration that RANKL-mediated induction of vM prior to oral immunization is a novel and effective strategy capable of enhancing the potency of mucosal vaccines.