Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by Type I and Type II heat-labile enterotoxins

Abstract

The heat-labile enterotoxins (HLT) expressed by Vibrio cholerae (cholera toxin) and Escherichia coli (LT-I, LT-IIa, and LT-IIb) are potent systemic and mucosal adjuvants. Co-administration of the enterotoxins with a foreign antigen (Ag) produces an augmented immune response to that antigen. Although each enterotoxin has potent adjuvant properties, the means by which the enterotoxins induce various immune responses are distinctive for each adjuvant. Various mutants have been engineered to dissect the functions of the enterotoxins required for their adjuvanticity. The capacity to strongly bind to one or more specific ganglioside receptors appears to drive the distinctive immunomodulatory properties associated with each enterotoxin. Mutant enterotoxins with ablated or altered ganglioside binding affinities have been employed to investigate the role of gangliosides in enterotoxin-dependent immunomodulation.

Glycosphingolipid Functions

“…GM1 accumulates in microdomains, both in model (de Almeida et al 2005), and plasma membrane bilayers (Chinnapen et al 2007) CTx B subunit provides mucosal adjuvant activity via GM1 binding-mediated signal transduction (Schnitzler et al 2007), largely independent of A subunit action, and has been used in clinical trials (Sun et al 2010). This adjuvant property is shared with the ganglioside binding E.coli heat labile toxins (Connell 2007). GM1 binding (crosslinking) is key to their immunomodulatory activity.…”

Simultaneous Exposure to Escherichia coli Heat-Labile and Heat-Stable Enterotoxins Increases Fluid Secretion and Alters Cyclic Nucleotide and Cytokine Production by Intestinal Epithelial Cells

“…ETEC produces two classes of heat-labile enterotoxins, types I and II (9). Each type is differentiated by genetic, biochemical, and immunological characteristics.…”

Recent advances in the development of novel mucosal adjuvants and antigen delivery systems

“…It is widely acknowledged that binding of CT/LT through CTB/LTB to G M1 ganglioside receptors on mucosal epithelial cells, M cells, DCs, and macrophages is important for antigen presentation. 83 To our knowledge, there are no reports on whether CTA/LTA alone or CTB/LTB with reduced receptor binding activity are functional adjuvants. Results from such investigations would provide direct evidence of the role of B-subunits in the mucosal adjuvanticity induced by CT/LT.…”