Ayako Wakabayashi
Nippon Medical School, Japan
Title: HMGB1 released from damaged intestinal epithelia contributes to activation of mucosal DCs and induction of intestinal CTLs and IgA
Biography
Biography: Ayako Wakabayashi
Abstract
Cholera toxin (CT) is a potent mucosal adjuvant and oral administration of antigens plus intact CT but not CTA or CTB subunit induces antigen-specific CD8+ CTLs as well as IgA production in intestinal mucosa; however, mechanisms for the induction of these immune responses remain unknown. We attempted to examine whether oral administration of CT induces enhancement of intestinal cell death and release of HMGB1. The number of viable intestinal epithelial cells (IECs) was remarkably reduced and the number of dying AnnexinV+ 7-AAD+ cells was significantly increased in EpCAM+ IECs at 16 h after the oral administration of intact CT, compared to the group with oral CTA or CTB subunit. Then, we observed a significant increase of the fecal HMGB1 levels at 6 and 16 h after the oral CT-stimulation compared to other groups. After that, we tried to examine whether cytoplasmic HMGB1+ IECs are increased by the oral CT-stimulation. The cytoplasmic HMGB1+ IECs were significantly increased by the oral CT-stimulation and they were EpCAM+CD45- IECs. HMGB1 dose-dependently enhanced the expression of CD80 and CD86 on DCs in vitro, and intravenous or oral administration of glycyrrhizin, an HMGB1 inhibitor, significantly suppressed activation of mucosal DCs, induction of intestinal CTLs and IgA, and DTH responses by oral CT-stimulation. Taken together, these results suggest that oral administration of intact CT but not CTA or CTB subunit triggers epithelial cell death in the gut and the release of HMGB1 from damaged IECs and that the released HMGB1 may mediate activation of mucosal DCs and induction of CTLs and IgA in the intestine.