Modulation of innate and acquired immune responses by Escherichia coli heat-labile toxin: Distinct pro- and anti-inflammatory effects of the nontoxicAB complex and the enzyme activity

We have examined the roles of enzyme activity and the nontoxic AB complex o f heat-labile toxin (LT) front Escherichia coli on its adjuvant and immunom odulatory properties. LTK63, an LT mutant that is completely devoid of enzy me activity, enhanced Th1 responses to coinjected Ags at low adjuvant dose, In contrast, LTR72, a partially detoxified mutant, enhanced Th2 responses and when administered intranasally to mice before infection with Bordetella pertussis suppressed Th1 responses and delayed bacterial clearance from th e lungs. LTR72 or wild-type LT inhibited Ag-induced IFN-gamma production by Th1 cells, and LT enhanced IL-5 production by Th2 cells in vitro. Each of the toxins enhanced B7-1 expression on macrophages, but enhancement of B7-2 expression was dependent on enzyme activity, We also observed distinct eff ects of the nontoxic AB complex and enzyme activity on inflammatory cytokin e production, LT and LTR72 suppressed LPS and IFN-gamma induced TNF-alpha a nd IL-12 production, but enhanced IL-10 secretion by macrophages in vitro a nd suppressed IL-12 production in vivo in a murine model of LPS-induced sho ck. In contrast, LTK63 augmented the production of IL-12 and TNF-alpha. Fur thermore, LTK63 enhanced NF-kappaB translocation, whereas low doses of LTR7 2 or LT failed to activate NF-kappaB, but stimulated cAMP production. Thus, E.coli LT appears to be capable of suppressing Th1 responses and enhancing Th2 responses through the modulatory effects of enzyme activity on NF-kapp aB activation and IL-12 production. In contrast, the nontoxic AB complex ca n stimulate acquired immune responses by activating components of the innat e immune system.