UC San Diego

Cholera toxin (CT), the causative factor responsible for the life-threatening acute diarrhea caused by Vibrio cholerae, is also well known as a potent mucosal vaccine adjuvant. However, little is known about the cellular and molecular mechanisms that mediate the mucosal adjuvant properties of CT. Recent studies have shown that Th17 cells discovered at mucosal sites have important role in generating strong immune responses that can be either protective (e.g. antimicrobial immunity) or destructive (e.g. autoimmune diseases EAE). Here, we showed that CT activates dendritic cells (DC) via cAMP-dependent mechanisms to drive the differentiation of naïve T cells into IL-17-producing Th17 cells in vitro and in vivo. Importantly, we identified an alternative pathway for Th17 differentiation that depends on the CT-induced secretion of calcitonin gene-related peptide (CGRP) by DC but is independent of IL-6. CGRP, a neuropeptide, in turn activates cAMP-dependent pathways in T cells that contribute to the generation of Th17 cells. These findings implicate Th17 induction as a contributing factor to the adjuvant effects of CT and identify novel pathways involved in T cell differentiation at mucosal sites.