title: Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses.
abstract: In an effort to develop a safe and effective vaccine against respiratory syncytial virus (RSV), we used Escherichia coli heat-labile toxin (LT), and LTK63 (an LT mutant devoid of ADP-ribosyltransferase activity) to elicit murine CD8(+) CTL responses to an intranasally codelivered CTL peptide from the second matrix protein (M2) of RSV. M2(82-90)-specific CD8(+) T cells were detected by IFN-gamma enzyme-linked immunospot and (51)Cr release assay in local and systemic lymph nodes, and their induction was dependent on the use of a mucosal adjuvant. CTL elicited by peptide immunization afforded protection against RSV challenge, but also enhanced weight loss. CTL-mediated viral clearance was not dependent on IFN-gamma since depletion using specific mAb during RSV challenge did not affect cellular recruitment or viral clearance. Depletion of IFN-gamma did, however, reduce the concentration of TNF detected in lung homogenates of challenged mice and largely prevented the weight loss associated with CTL-mediated viral clearance. Mice primed with the attachment glycoprotein (G) develop lung eosinophilia after intranasal RSV challenge. Mucosal peptide vaccination reduced pulmonary eosinophilia in mice subsequently immunized with G and challenged with RSV. These studies emphasize that protective and immunoregulatory CD8(+) CTL responses can be mucosally elicited using enterotoxin-based mucosal adjuvants but that resistance against viral infection may be accompanied by enhanced disease.
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: T
authors.initials: T
authors.lastname: Hussell
authors.forename: T
authors.initials: T
authors.lastname: Sparer
authors.forename: G
authors.initials: G
authors.lastname: Walzl
authors.forename: P
authors.initials: P
authors.lastname: Openshaw
authors.forename: G
authors.initials: G
authors.lastname: Dougan
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology*; D004802:Eosinophilia / Q000276:immunology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D029968:Escherichia coli Proteins; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000517:prevention & control; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D013552:Swine; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014764:Viral Proteins / Q000008:administration & dosage / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D010446:Peptide Fragments; D014764:Viral Proteins; D014765:Viral Vaccines; D007371:Interferon-gamma; C027538:heat-labile enterotoxin, E coli