title: MHC class I-restricted cytotoxic lymphocyte responses induced by enterotoxin-based mucosal adjuvants.
abstract: The ability of enterotoxin-based mucosal adjuvants to induce CD8+ MHC class I-restricted CTL responses to a codelivered bystander Ag was examined. Escherichia coli heat-labile toxin (LT), or derivatives of LT carrying mutations in the A subunit (LTR72, LTK63), were tested in parallel with cholera toxin (CT) or a fusion protein consisting of the A1 subunit of CT fused to the Ig binding domain of Staphylococcus aureus protein A (called CTA1-DD). Intranasal (i.n.) immunization of C57BL/6 mice with CT, CTA1-DD, LT, LTR72, LTK63, but not rLT-B, elicited MHC class I-restricted CD8+ T cell responses to coadministered OVA or the OVA CTL peptide SIINFEKL (OVA257-264). CT, LT, and LTR72 also induced CTL responses to OVA after s.c. or oral coimmunization whereas LTK63 only activated responses after s.c. coimmunization. rLT-B was unable to adjuvant CTL responses to OVA or OVA257-264 administered by any route. Mice treated with an anti-CD4 mAb to deplete CD4+ T cells mounted significant OVA-specific CTL responses after i.n. coadministration of LT with OVA or OVA257-264. Both 51Cr release assays and IFN-gamma enzyme-linked immunospot assays indicated that IFN-gamma-/- and IL-12 p40-/- gene knockout mice developed CTL responses equivalent to those detected in normal C57BL/6 mice. The results highlight the versatility of toxin-based adjuvants and suggest that LT potentiates CTL responses independently of IL-12 and IFN-gamma and probably by a mechanism unrelated to cross-priming.
authors.affiliation: Department of Biochemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, United Kingdom. c.simmons@ic.ac.uk
authors.forename: C P
authors.initials: CP
authors.lastname: Simmons
authors.forename: P
authors.initials: P
authors.lastname: Mastroeni
authors.forename: R
authors.initials: R
authors.lastname: Fowler
authors.forename: M
authors.initials: M
authors.lastname: Ghaem-maghami
authors.forename: N
authors.initials: N
authors.lastname: Lycke
authors.forename: M
authors.initials: M
authors.lastname: Pizza
authors.forename: R
authors.initials: R
authors.lastname: Rappuoli
authors.forename: G
authors.initials: G
authors.lastname: Dougan
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000284:Administration, Oral; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D002772:Cholera Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D029968:Escherichia coli Proteins; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D008213:Lymphocyte Activation; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000276:immunology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D015395:Histocompatibility Antigens Class I; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D000246:Adenosine Diphosphate Ribose; D007371:Interferon-gamma; D010047:Ovalbumin; D002772:Cholera Toxin; D001120:Arginine; C027538:heat-labile enterotoxin, E coli; D008239:Lysine