Genetically manipulated bacterial toxin as a new generation mucosal adjuvant.
Cholera toxin (CT) and heat-labile toxin (LT) of Escherichia coli act as adjuvants for the enhancement of mucosal and serum antibody (Ab) responses to mucosally co-administered protein antigen (Ag). Both LT and CT induce B7-2 expression on antigen-presenting cells (APCs) for subsequent co-stimulatory signalling to CD4+ T cells. CT directly affects CD4+ T cells activated via the TCR-CD3 complex with selective inhibition of Th1 responses whereas LT maintains Th1 cytokine responses with inhibition of interleukin (IL)-4 production. Interestingly, while CT failed to induce mucosal adjuvant activity in the absence of IL-4, LT did so. Nontoxic mutant (m)CTs (S61F and E112K) retain adjuvant properties by inducing CD4+ Th2 cells, which provided effective help for the Ag-specific mucosal immunoglobulin (Ig)A, as well as serum IgG1, IgE and IgA Ab responses. The mCT E112K has been shown to exhibit two distinct mechanisms for its adjuvanticity. Firstly, mCT enhanced the B7-2 expression of APCs. Secondly, this nontoxic CT derivative directly affected CD4+ T cells and selectively inhibited Th1 cytokine responses. Thus, several lines of evidence indicate that enzyme activity can be separated from adjuvant properties of CT and this offers promise for the development of safe delivery of vaccines for mucosal IgA responses.
Yamamoto
M
M
Department of Clinical Pathology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba 271-8587, Japan.
McGhee
J R
JR
Hagiwara
Y
Y
Otake
S
S
Kiyono
H
H
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D051940:B7-2 Antigen; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002772:Cholera Toxin / Q000235:genetics / Q000494:pharmacology*; D004768:Enterotoxins / Q000235:genetics / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D005818:Genetic Engineering; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects*; D015847:Interleukin-4 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009154:Mutation
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D051940:B7-2 Antigen; D001427:Bacterial Toxins; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D008562:Membrane Glycoproteins; D015847:Interleukin-4; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli