he mucosal surfaces of the body are constantly exposed to a myriad of benign foreign antigens that are acquired through eating, breathing and touching, among others. Superficially, environmental or food antigens appear to be substantially ignored by the healthy immune system, which regards them as harmless. Indeed, we might actually show measurable immunological tolerance to them 1 . Relatively few molecules are highly immunogenic when they contact mucosal surfaces, in the sense that they generate strong humoral and secretory antibody responses. Such molecules are often referred to as mucosal immunogens.
The most powerful mucosal immunogens that are recognized to date are cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT), the molecules that cause the debilitating watery secretions typical of cholera and traveller's diarrhoea, respectively 2,3 . The mucosal immune system somehow recognizes that these toxins are a threat and, a short time after they make contact with a mucosal surface, a powerful immune response is mounted against them. This antitoxin response is so potent that sometimes a strong and easily measurable immune response is also activated against foreign bystander molecules that are present simultaneously at the mucosal surface 4 .
As a consequence of this immunopotentiating property, CT and LT have been investigated extensively and exploited as mucosal immunogens and adjuvants in animal models 5,6 . However, the high toxicity of CT and LT makes them unsuitable for practical human use 2 , thus prompting recent efforts to dissect the mucosal immunogenicity and adjuvanticity of CT and LT from their toxicity. Site-directed mutagenesis, guided by the crystal structure of the molecule and coupled with molecular modelling 7 , has clarified our understanding of what makes these molecules so special in terms of mucosal immunity by disclosing the role of the receptorbinding domain, the B subunit, the A subunit and the enzymatic activity of LT and CT (Ref. 8). Critically, the use of highly purified recombinant material has also clarified compromised observations made previously with toxin-contaminated LT and CT B subunit derivatives (LTB and CTB, respectively) .
The relationship between structure and function of LT and CT
CT and LT belong to the AB class of bacterial toxins 11 . The two molecules have high homology (80% identity) in their primary structure and superimposable tertiary structures 14 . Both toxins are composed of a pentameric B oligomer that binds the receptor(s) on the surface of eukaryotic cells, and an enzymatically active A subunit that is responsible for the toxicity (Fig. ).