Modulation of T cell responses by manipulating signalling pathways in dendritic cells

Abstract

Heat labile enterotoxin from E. Coli (LT) is a powerful vaccine adjuvant, capable of enhancing Th1 and Th2 responses to co-administered antigens. The present study demonstrates that LT also promotes the induction of Th17 cells. The ability of LT to promote the induction of IL-17-producing T cells (Th17 cells) was mediated in part by modulation of dendritic cell (DC) activation. LT induced IL-23p19 mRNA expression in DC and enhanced TLR-induced IL-23 secretion. The adjuvanticity and immunomodulatory potential of LT has largely been attributed to the ADP- ribosyltransferase activity associated with the A subunit, and consequent accumulation of intracellular cAMP. However, studies with the B subunit and LT mutants lacking enzyme activity demonstrated that these retained adjuvant properties. The findings of this study demonstrate that LTR72, a partially enzymatically active derivative of LT, also promoted the induction of Th17 cells, as did LTK63, an enzymatically inactive mutant, albeit to a lesser extent. LTR72 and LTK63 induced IL-23p19 mRNA expression and enhanced TLR-induced IL-23 production by DC.