Th1-promoting adjuvanticity of cholera toxin depends on Gsα in CD11b+ dendritic cells (VAC10P.969)

Abstract

Abstract Despite an extensive literature on the mechanisms of action of cholera toxin (CT) we still lack critical information about how CT augments immune responses. Although several studies have identified dendritic cells (DC) as critical target cells for the adjuvant function there is still not a distinct subset of DCs that has been shown to convey the adjuvant effect. Even more confusing is the fact CT has been considered a strong Th2-skewing adjuvant, but many researchers have found potent IFNγ and Th1 promoting function, despite that CT interferes with IRF8 and blocks IL-12 production. We immunized wild-type, Batf3-/- (lacking CD8α+ DCs) and Cre-lox mice with a CD11c -selective defect in Gsα, the membrane target protein for CT’s ADP-ribosylation. While CT exerted extensive global effects on secondary lymphoid tissues with recruitment and redistribution of both innate and adaptive immunocytes leading to a complete loss of CD4 T cell priming ability, this condition was effectively restored by transferring freshly isolated CD11c+ DCs. As Batf3-/- mice exhibited intact adjuvanticity, CD8α+ DCs were not required for the adjuvant effect. However, we found that CD11b+CD11c+ cells were absolutely needed and that Gsα-expression was critical. CD4 T cell priming was unrestricted and Th1, Th2 and Th17 differentiation was observed also in the absence of IL-12, arguing that CT exerts an adjuvant effect independent of IRF8.