Cholera toxin, E. coli heat-labile toxin, and non-toxic derivatives induce dendritic cell migration into the follicle-associated epithelium of Peyer's patches

Abstract

The follicle-associated epithelium (FAE) of Peyer's patches (PPs) transports antigens and microorganisms into mucosal lymphoid tissues where they are captured by subepithelial dendritic cells (DCs). Feeding of cholera toxin (CT) induced migration of subepithelial DCs to interfollicular T-cell areas within 24 h. This study investigated short-term effects of CT, Escherichia coli heat-labile toxin, and non-toxic derivatives on DC migration. CT or CTB injected into ligated intestinal loops induced significant increase in CD11c + DCs within the FAE within 90 min. In mice fed CT intragastrically, DC numbers in the FAE increased by 1 h, were maximal by 2 h, declined between 8 and 12 h, and were reversed by 24 h. Feeding of native LT, recombinant CTB, dibutyryl cyclic AMP, and to a lesser extent mutated CT(E29H) or mutated LT(R192G) had the same effect. Thus, both A and B subunits of enterotoxins, presumably acting through distinct signaling pathways, may promote capture of incoming antigens and pathogens by PP DCs.

Identification and Characterization of Intestinal Antigen-Presenting Cells Involved in Uptake and Processing of a Nontoxic Recombinant Chimeric Mucosal Immunogen Based on Cholera Toxin Using Imaging Flow Cytometry

“…The uptake of antigens by intestinal APC is a highly dynamic process, as revealed by the marked fluctuations of DC numbers in both PP and LP regardless of whether they contained detectable antigen. Rapid migration of DC into the dome region of PP followed by withdrawal within 12 h has been observed after intestinal delivery of CT (22). Our findings are consistent with the concept that DC become mobilized by cytokines released into the environment of the inductive site as a result of antigen uptake.…”

Mucosal Immunization with a Staphylococcus aureus IsdA-Cholera Toxin A2/B Chimera Induces Antigen-Specific Th2-Type Responses in Mice

“…Our results demonstrate that IsdA-CTA 2 /B can be expressed efficiently in E. coli and bind to ganglioside GM1 in vitro. GM1 is found ubiquitously on mammalian cells, but immune effector cells, such as dendritic cells, have a uniquely high affinity for CT and nontoxic CTB (2,30). The binding and transport of IsdA-CTA 2 /B into epithelial and dendritic cells were consistent with the uptake of native CT involving retrograde movement to the perinuclear domain of the Golgi apparatus and endoplasmic reticulum (5,39,55).…”

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

“…However, in the absence of the structural stability provided by the B subunit, it is unclear how isolated A subunit functions as an adjuvant. Traditionally, the adjuvanticity of LT-based adjuvants is thought to be related to induction of intracellular cAMP, as some of the in vitro effects can be mimicked by cAMP analogs or derivatives (1,2,47). Moreover, molecules that are completely enzymatically inactive are less effective as mucosal adjuvants than those that retain at least a minimal level of cAMP activity (7,36,39).…”

“…Administration of LT by virtually any mucosal route first activates innate immune responses, including secretion of inflammatory cytokines, dendritic cell (DC) recruitment and activation, and initiation of antigen presentation (1,21,47,50,54). 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).…”