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By
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From the * Immunobiology Vaccine Center and Department of Microbiology and Department of Oral
Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294; Cholera toxin (CT), the most commonly used mucosal adjuvant in experimental animals, is
unsuitable for humans because of potent diarrhea-inducing properties. We have constructed
two CT-A subunit mutants, e.g., serine Department of
Microbiology, Faculty of Medicine, Kyoto University, Kyoto 606, Japan; § Research Institute,
International Medical Center of Japan, Shinjuku-ku, Tokyo 162, Japan; Second Department of
Microbiology, Faculty of Medicine, Chiba University, Chuo-ku, Chiba 260, Japan; and ¶ Department
of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka
565, Japan
phenylalanine at position 61 (S61F), and glutamic
acid lysine at 112 (E112K) by site-directed mutagenesis. Neither mutant CT (mCT), in contrast to native CT (nCT), induced adenosine diphosphate-ribosylation, cyclic adenosine monophosphate formation, or fluid accumulation in ligated mouse ileal loops. Both mCTs retained
adjuvant properties, since mice given ovalbumin (OVA) subcutaneously with mCTs or nCT,
but not OVA alone developed high-titered serum anti-OVA immunoglobulin G (IgG) antibodies (Abs) which were largely of IgG1 and IgG2b subclasses. Although nCT induced brisk
IgE Ab responses, both mCTs elicited lower anti-OVA IgE Abs. OVA-specific CD4+ T cells
were induced by nCT and by mCTs, and quantitative analysis of secreted cytokines and
mRNA revealed a T helper cell 2 (Th2)-type response. These results now show that the toxic
properties of CT can be separated from adjuvanticity, and the mCTs induce Ab responses via a
Th2 cell pathway.
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