Cholera toxin activates dendritic cells through dependence on GM1-ganglioside which is mediated by NF-kappaB translocation.
Cholera toxin (CT) is a potent adjuvant; however, the mechanism for its ability to enhance mucosal immunity has not been fully elucidated. We report here that CT exerts its adjuvant properties by signaling through the GM1 ganglioside receptor. When ganglioside-defective mice were given the antigen (Ag) ovalbumin (OVA) with CT by the oral route, CT failed to support either OVA-specific antibody or CD4+ T cell responses. In vitro treatment of murine bone marrow-derived dendritic cells (DC) with CT induced full maturation as evidenced by up-regulation of the costimulatory molecules, as well as by an enhanced ability to effectively present OVA for Ag-specific T cell responses. On the other hand, ganglioside-defective DC failed to differentiate to full function as Ag-presenting cells in response to CT. Since ganglioside-defective DC showed a mature phenotype after stimulation with lipopolysaccharide (LPS), the effects of CT on DC was independent of signal transduction through adjuvant receptor for LPS, the Toll-like receptor 4. Furthermore, CT also induced nuclear translocation of nuclear factor (NF)-kappaB in DC in a GM1-dependent fashion. These results highlight gangliosides expressed by DC for recognition of the non-self protein bacterial enterotoxin, which employ a unique signaling pathway to induce both innate and adaptive immunity.
Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Yuki I
YI
Kawamura
Rei
R
Kawashima
Yuko
Y
Shirai
Rie
R
Kato
Takashi
T
Hamabata
Masafumi
M
Yamamoto
Koichi
K
Furukawa
Kohtaro
K
Fujihashi
Jerry R
JR
McGhee
Hideo
H
Hayashi
Taeko
T
Dohi
D000818:Animals; D002772:Cholera Toxin / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005732:Gangliosides / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*
D005732:Gangliosides; D016328:NF-kappa B; C025447:sialogangliosides; D002772:Cholera Toxin; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase