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,
,
*
Department of Clinical Pathology, Nihon University School of Dentistry, Matsudo, Japan;
Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
Departments of Oral Biology and Microbiology, Immunobiology Vaccine Center, University of Alabama Medical Center, Birmingham, AL 35294;
§
Department of Immunology, National Children’s Medical Research Center, Tokyo, Japan; and
¶
Research Institute, International Medical Center of Japan, Tokyo, Japan
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-
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-
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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