Potent immunogenicity of the B subunits of Escherichia coli heat-labile enterotoxin: receptor binding is essential and induces differential modulation of lymphocyte subsets.

Nashar, Toufic O.; Webb, Helen; Eaglestone, Simon; Williams, Neil; Hirst, Timothy R.

doi:10.1073/pnas.93.1.226

Cited by 136 publications

(158 citation statements)

References 35 publications

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“…In order for a protein to be orally immunogenic, it must be taken up by the intestinal epithelium to gain access to the mucosal immune system. In the case of CTB and LTB the uptake is believed to be largely receptor-mediated , and the non-GM1-binding mutant of LTB, EtxB(G33D), was recently found to be orally non-immunogenic in mice (Nashar et al, 1996). Recent experiments indicate that CTB is a better oral immunogen than LTB, although the proteins are equally good immunogens after intranasal or parenteral administrations (C. Rask et al, unpublished).…”

Section: Discussionmentioning

confidence: 99%

“…The hybrid B-subunits, and the parent CTB and LTB proteins, were compared in their ability to bind to (i) delipidized intestinal cell membranes, (ii) a mixture of both GM1 and non-GM1 glycosphingolipids (GSL), and (iii) PGCs, all prepared from rabbit small intestine, as well as to relevant purified glycosphingolipids. We also investigated the binding properties of a mutant LTB carrying a Gly→Asp substitution at position 33, EtxB(G33D), as this mutation was previously reported to completely abolish the GM1-binding activity of both CTB (Jobling and Holmes, 1991) and LTB (Nashar et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for differential receptor binding of cholera and Escherichia coli heat‐labile toxins: influence of heterologous amino acid substitutions in the cholera B‐subunit

Bäckström

Shahabi

Johansson

et al. 1997

Molecular Microbiology

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SummaryThe closely related B-subunits of cholera toxin (CTB) and Escherichia coli heat-labile enterotoxin (LTB) both bind strongly to GM1 ganglioside receptors but LTB can also bind to additional glycolipids and glycoproteins. A number of mutant CT B-subunits were generated by substituting CTB amino acids with those at the corresponding positions in LTB. These were used to investigate the influence of specific residues on receptor-binding specificity. A mutated CTB protein containing the first 25 residues of LTB in combination with LTB residues at positions 94 and 95, bound to the same extent as native LTB to both delipidized rabbit intestinal cell membranes, complex glycosphingolipids (polyglycosylceramides) and neolactotetraosylceramide, but not to non-GM1 intestinal glycosphingolipids. In contrast, when LTB amino acid substitutions in the 1-25 region were combined with those in the 75-83 region, a binding as strong as that of LTB to intestinal glycosphingolipids was observed. In addition, a mutant LTB with a single Gly-33→Asp substitution that completely lacked affinity for both GM1 and non-GM1 glycosphingolipids could still bind to receptors in the intestinal cell membranes and to polyglycosylceramides. We conclude that the extra, non-GM1 receptors for LTB consist of both sialylated and non-sialylated glycoconjugates, and that the binding to either class of receptors is influenced by different amino acid residues within the protein.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural basis for differential receptor binding of cholera and Escherichia coli heat‐labile toxins: influence of heterologous amino acid substitutions in the cholera B‐subunit

Bäckström

Shahabi

Johansson

et al. 1997

Molecular Microbiology

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“…Moreover, non-toxic B subunits of these toxins (CTB, LTB), which have strong binding capacity to GM 1 gangliosides, have been investigated about their adjuvanticity in these years and have been shown to induce both systemic and mucosal immune response in all mucosal tissues to some mucosally co-administered antigens (20,27,30). However, oral administration of CTB chemically coupled to antigens is known to induce tolerance, such as inhibition of acute GVHD and prevention of autoimmune diabetes (26,31).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Cholera Toxin B Subunit Activates Dendritic Cells and Enhances Antitumor Immunity

Isomura

Yasuda

Tsujimura

et al. 2005

Microbiology and Immunology

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Activation of dendritic cells (DC) is crucial for priming of cytotoxic T lymphocytes (CTL), which have a critical role in tumor immunity, and it is considered that adjuvants are necessary for activation of DC and for enhancement of cellular immunity. In this study, we examined an adjuvant capacity of recombinant cholera toxin B subunit (rCTB), which is non‐toxic subunit of cholera toxin, on maturation of murine splenic DC. After the in vitro incubation of DC with rCTB, the expression of MHC class II and B7–2 on DC was upregulated and the secretion of IL‐12 from DC was enhanced. In addition, larger DC with longer dendrites were observed. These data suggest that rCTB induced DC maturation. Subsequently, we examined the induction of tumor immunity by rCTB‐treated DC by employing Meth A tumor cells in mice. Pretreatment with subcutaneous injection of rCTB‐treated DC pulsed with Meth A tumor lysate inhibited the growth of the tumor cells depending on the number of DC. Moreover, intratumoral injection of rCTB‐treated DC pulsed with tumor lysate had therapeutic effect against established Meth A tumor. Immunization with DC activated by rCTB and the tumor lysate increased number of CTL precursor recognizing Meth A tumor. The antitumor immune response was significantly inhibited in CD8+ T cell‐depleted mice, although substantial antitumor effect was observed in CD4+ T cell‐depleted mice. These results indicated that rCTB acts as an adjuvant to enhance antitumor immunity through DC maturation and that CD8+ T cells play a dominant role in the tumor immunity. Being considered to be safe, rCTB may be useful as an effective adjuvant to raise immunity for a tumor in clinical application.

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“…LT and CT have been reported to induce selective apoptosis of CD8 + T cells, naïve cells being more sensitive than activated cells [57,151,175].…”

Section: Cholera Toxin and Escherichia Coli Thermolabile Enterotoxinmentioning

confidence: 99%

Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa

et al. 2006

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-In developing veterinary mucosal vaccines and vaccination strategies, mucosal adjuvants are one of the key players for inducing protective immune responses. Most of the mucosal adjuvants seem to exert their effect via binding to a receptor/or target cells and these properties were used to classify the mucosal adjuvants reviewed in the present paper: (1) ganglioside receptor-binding toxins (cholera toxin, LT enterotoxin, their B subunits and mutants); (2) surface immunoglobulin binding complex CTA1-DD; (3) TLR4 binding lipopolysaccharide; (4) TLR2-binding muramyl dipeptide; (5) Mannose receptor-binding mannan; (6) Dectin-1-binding ß 1,3/1,6 glucans; (7) TLR9-binding CpG-oligodeoxynucleotides; (8) Cytokines and chemokines; (9) Antigen-presenting cell targeting ISCOMATRIX and ISCOM. In addition, attention is given to two adjuvants able to prime the mucosal immune system following a systemic immunization, namely 1α, 25(OH) 2 D 3 and cholera toxin.

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Potent immunogenicity of the B subunits of Escherichia coli heat-labile enterotoxin: receptor binding is essential and induces differential modulation of lymphocyte subsets.

Cited by 136 publications

References 35 publications

Structural basis for differential receptor binding of cholera and Escherichia coli heat‐labile toxins: influence of heterologous amino acid substitutions in the cholera B‐subunit

Structural basis for differential receptor binding of cholera and Escherichia coli heat‐labile toxins: influence of heterologous amino acid substitutions in the cholera B‐subunit

Recombinant Cholera Toxin B Subunit Activates Dendritic Cells and Enhances Antitumor Immunity

Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa

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