LT-IIc, a new member of the type II heat-labile enterotoxin family, exhibits potent immunomodulatory properties that are different from those induced by LT-IIa or LT-IIb

Abstract

A plethora of human pathogens invade and/or colonize mucosal surfaces. Elaboration of strong, protective immune responses against those pathogens by mucosal vaccination, however, is hampered by endogenous regulatory systems in the mucosae that dampen responses to foreign antigens (Ags). To overcome those natural barriers, mucosal adjuvants must be employed. Using a mouse mucosal immunization model and AgI/II, a weak immunogen from Streptococcus mutans, LT-IIc, a new member of the type II subgroup of the heat-labile enterotoxin family, was shown to have potent mucosal adjuvant properties. In comparison to mice intranasally immunized only with AgI/II, co-administration of AgI/II with LT-IIc enhanced production of Ag-specific IgA antibodies in the saliva and vaginal fluids and Ag-specific IgA and IgG in the serum. Secretion of IL-2, IL-6, IL-17, IFN-γ, and TNF-α was enhanced in cultures of AgI/II-stimulated splenic cells isolated from mice that had received LT-IIc as a mucosal adjuvant. In contrast, secretion of IL-10 was suppressed in those cells. This pattern of cytokine secretion suggested that LT-IIc stimulates both Th1 and Th2 immune responses. In contrast to LT-IIa and LT-IIb, the original members of the type II subgroup that also are mucosal adjuvants, LT-IIc dramatically enhanced secretion of IL-1α and IL-1β in peritoneal macrophages that had been co-cultured with LPS. Furthermore, the B pentameric subunit of LT-IIc augmented uptake of Ag by bone marrow-derived dendritic cells to levels that exceeded those attained by use of LPS or by the B pentamers of LT-IIa or LT-IIb. These data confirmed that LT-IIc is a strong mucosal adjuvant with immunomodulatory properties that are distinguishable from those of LT-IIa and LT-IIb and which has immunomodulatory properties that may be exploitable in vaccine development.