Non-toxic Stx derivatives from Escherichia coli possess adjuvant activity for mucosal immunity.
Both B subunit of Shiga toxin 1 (Stx1-B), which mediates the binding of toxin to the membrane, and mutant Stx1 (mStx1), which is a non-toxic double-mutated Stx1 harboring double amino acid substitutions in the A subunit, possess potent mucosal adjuvant activity. Nasal immunization of mice with ovalbumin (OVA) plus the Stx1-B or mStx1 induced OVA-specific serum IgG and mucosal IgA responses. IgG subclass analysis revealed that mStx1 and Stx1-B as mucosal adjuvants supported Ag-specific IgG1 followed by IgG2b Abs. The co-administration of either mStx1 or Stx1-B with OVA enhanced the production of IL-4, IL-5, IL-6 and IL-10 with low IFN-gamma, by OVA-specific CD4+ T cells. To better elucidate the mechanisms underlying mStx1's and Stx1-B's adjuvant activity, we next sought to examine whether or not dendritic cells (DC) residing in the nasopharyngeal-associated lymphoreticular tissue (NALT) were activated by nasal administration of Stx1-B or mStx1. We found that mice nasally administered with Stx1-B or mStx1 showed an up-regulation in the expression of CD80, CD86 and especially CD40 on NALT DCs. Taken together, these results suggest that non-toxic Stx derivatives could be effective mucosal adjuvants for the induction of Th2-type, CD4+ T cell mediated, antigen-specific mucosal IgA and systemic IgG Ab responses, and that they likely owe their adjuvant activity to the up-regulation of co-stimulatory molecules including CD80, CD86 and CD40 on NALT DCs.
Department of Microbiology and Immunology, Division of Mucosal Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Mari
M
Ohmura-Hoshino
Masafumi
M
Yamamoto
Yoshikazu
Y
Yuki
Yoshifumi
Y
Takeda
Hiroshi
H
Kiyono
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000276:immunology / Q000517:prevention & control; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000187:drug effects; D018928:Immunity, Mucosal / Q000187:drug effects*; D007115:Immunization Schedule; D008214:Lymphocytes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009305:Nasopharynx / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D022622:Shiga Toxin 1 / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D022622:Shiga Toxin 1; D010047:Ovalbumin