Cholera-Like Enterotoxins and Regulatory T cells

Abstract

Cholera toxin (CT) and the heat-labile enterotoxin of E. coli (LT), as well as their non toxic mutants, are potent mucosal adjuvants of immunization eliciting mucosal and systemic responses against unrelated co-administered antigens in experimental models and in humans (non toxic mutants). These enterotoxins are composed of two subunits, the A subunit, responsible for an ADP-ribosyl transferase activity and the B subunit, responsible for cell binding. Paradoxically, whereas the whole toxins have adjuvant properties, the B subunits of CT (CTB) and of LT (LTB) have been shown to induce antigen specific tolerance when administered mucosally with antigens in experimental models as well as, recently, in humans, making them an attractive strategy to prevent or treat autoimmune or allergic disorders. Immunomodulation is a complex process involving many cell types notably antigen presenting cells and regulatory T cells (Tregs). In this review, we focus on Treg cells and cholera-like enterotoxins and their non toxic derivates, with regard to subtype, in vivo/in vitro effects and possible role in the modulation of immune responses to coadministered antigens.

Mucosal Adjuvants

“…The effect of the B subunits on immune cell is controversial, and many reports indicate their tendency to have tolerogenic or repressive functions (Sun et al, 2012;Basset et al, 2010;Sun et al, 2010). The varied and at times contradictory observations on the interaction of BAREs with immune cells indicate the powerful immunological effects of these adjuvants and their unquestionable ability to alter the immunophenotype, proliferation, function, and trafficking of immune cells.…”

The A Subunit of Escherichia coli Heat-Labile Enterotoxin Functions as a Mucosal Adjuvant and Promotes IgG2a, IgA, and Th17 Responses to Vaccine Antigens

“…Most evidence suggests that the ability of LT to function as a mucosal adjuvant is related to its ability to induce cAMP, and molecules that are completely enzymatically inactive are less effective as mucosal adjuvants than those that retain at least a minimal level of cAMP activation (7,36,39). The B subunit can itself promote immune responses to coadministered antigens, although these responses are less potent and more skewed toward Th2 and regulatory phenotypes than those seen with the holotoxin or certain AB5 mutants (3,20,32,52,56). The adjuvant properties of the B subunit have been difficult to clearly establish because many studies have been performed using B sub-unit isolated by dissociation chromatography and contaminated with small amounts of LT holotoxin or with lipopolysaccharide (LPS).…”

“…Subsequently, antigen-specific adaptive immune responses develop, including IgG1/IgG2a antibodies, mucosal IgA, and mixed Th1/ Th2/Th17/Treg cellular responses, depending upon the intrinsic nature of the coadministered antigen, the type of attenuating mutation to the LT (if any), and the route of immunization (3,6,13,24,37,41,42,53,55). The mechanisms through which LT functions as a mucosal adjuvant are not well understood, and conflicting results have been obtained by different investigators using different preparations of LT, different antigens, and different routes of immunization.…”

The Cholera Toxin as a Biotechnological Tool

“…In this regard, promising results have been obtained with auto-antigen coupled to CTB in order to induce oral tolerance. Although not known the mechanism by which CTB conjugated to antigens has the ability to potentiate the induction of oral tolerance, it is believed that in addition to the processes already mentioned before for CT, it may result in selected DC subsets with increased ability to induce different types of TGF--expressing suppressor T cells including CD4 + CD25 + Tr cells [Holmgren et al, 2005] and a direct depletion of effector T cells since CTB induces CD4+ and CD8+ T cell apoptosis [Christelle Basset, 2010].…”