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Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant.
Yamamoto, M; Kiyono, H; Yamamoto, S; Batanero, E; Kweon, M N; Otake, S; Azuma, M; Takeda, Y; McGhee, J R.
Afiliación
  • Yamamoto M; Department of Clinical Pathology, Nihon University School of Dentistry, Matsudo, Japan.
J Immunol ; 162(12): 7015-21, 1999 Jun 15.
Article en En | MEDLINE | ID: mdl-10358143
ABSTRACT
The present study has elucidated two distinct mechanisms that may explain how a mutant of cholera toxin (mCT), E112K, retains adjuvant effects though it lacks ADP-ribosyltransferase activity and associated toxicity. In the first mechanism, we show that mCT E112K, like native cholera toxin (nCT), enhances B7-2 expression, but, to some extent, also enhances B7-1 on Peyer's patch B cells and macrophages. Cocultivation of CD4+ T cells with E112K- or nCT-treated B cells and macrophages in the presence of anti-CD3 stimulation resulted in the induction of T cell-proliferative responses. Further, the responses were blocked by mAbs to B7-1 and/or B7-2; however, the effect of anti-B7-1 was minimal. In the second mechanism, addition of mCT E112K or nCT to anti-CD3 mAb-stimulated Peyer's patch CD4+ T cells inhibited proliferative responses, while recombinant CT-B subunit (rCT-B) did not. Analysis of cytokine responses showed that both mCT E112K and nCT preferentially inhibited IFN-gamma production. Interestingly, however, nCT, but not mCT E112K, induced apoptosis in CD4+ T cells activated via the TCR-CD3 complex. These results indicate that CT uses at least two pathways for inhibition of Th1 responses and that, while nCT induces cAMP accumulation that in turn leads to apoptosis in Th1-type cells, mCT E112K, which lacks ADP-ribosyltransferase activity, inhibits IFN-gamma synthesis by a separate mechanism. Thus, mCT E112K, like nCT, induces adjuvant responses via up-regulation of mainly B7-2 on APCs and through preferential inhibition of Th1-type CD4+ T cell responses in the absence of ADP-ribosyltransferase activity.
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Bases de datos: MEDLINE Asunto principal: Linfocitos T CD4-Positivos / Adyuvantes Inmunológicos / Toxina del Cólera / Células Presentadoras de Antígenos Idioma: En Revista: J Immunol Año: 1999 Tipo del documento: Article País de afiliación: Japón
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Bases de datos: MEDLINE Asunto principal: Linfocitos T CD4-Positivos / Adyuvantes Inmunológicos / Toxina del Cólera / Células Presentadoras de Antígenos Idioma: En Revista: J Immunol Año: 1999 Tipo del documento: Article País de afiliación: Japón