Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent.

Cholera toxin (CT) is a potent vaccine adjuvant when administered via parenteral, muco- sal, or transcutaneous routes. It also inhibits innate inflammatory responses induced by pathogen-de- rived molecules, such as lipopolysaccharide (LPS). We demonstrated previously that CT promotes the induction of regulatory type 1 T cells (Tr1) as well as T helper type 2 cells (Th2). T cells from mice immunized with antigen in the presence of CT pro- duced high levels of interleukin (IL)-10 and IL-5 and low levels of IL-4 and interferon- (IFN-). Here, we demonstrate that immunization with an- tigen in the presence of CT induced a population of antigen-specific CD4 T cells that produced IL-10 in the absence of IL-4, in addition to cells that coexpressed IL-4 and IL-10 or produced IL-4 only. CT-generated Tr1 cells inhibited antigen-spe- cific proliferation as well as IFN- production by Th1 cells, and this suppression was cell contact- independent. It is interesting that coincubation with Th1 cells significantly enhanced IL-10 pro- duction by the Tr1 cells. As IL-10 can promote the differentiation of Tr1 cells, we investigated cyto- kine production by dendritic cells (DC) following exposure to CT. Previous data showed that CT can modulate the expression of costimulatory mole- cules and inhibit the production of chemokines and cytokines, including IL-12 and tumor necrosis fac- tor and enhance IL-10 production. Here, we show that CT synergizes with LPS to induce IL-6 and IL-1 in addition to IL-10 production by im- mature DC. Therefore, CT may promote the in- duction of Th2 and Tr1 cells in part via selective modulation of DC cytokine production and co- stimulatory molecule expression. J. Leukoc. Biol. 75: 756-763; 2004.