Lipid-containing mimetics of natural triggers of innate immunity as CTL-inducing influenza vaccines.
Anti-viral CD8(+) T cell responses can be induced using synthetic lipopeptides and a range of different lipid moieties have been examined in a variety of model systems and in man for this purpose. Nevertheless, only limited data exist on comparative efficacy of different lipopeptides in a single model of protection so that the optimal composition for vaccination purposes remains unknown. In this study, we examined different lipid structures from bacterial or non-bacterial sources coupled to peptides representing influenza viral epitopes recognized by CD8(+) and CD4(+) T cells. These were assessed in the context of intra-nasal (i.n.) immunization in the absence of added adjuvant. The strongest immunogens were those containing bacterially derived lipids that induced dendritic cell (DC) maturation via Toll-like receptor 2 (TLR2) binding. The number of DCs induced to mature in vitro was directly associated with the strength of the CD8(+) T cell-mediated viral clearing responses in primed mice. Mice immunized with the TLR2-binding lipopeptides showed greatly enhanced numbers of specific IFN-gamma-secreting CD8(+) T cells at the site of infection after i.n. exposure to virus, which resulted in enhanced protection of the pneumonic lung. Importantly, lipopeptide-pulsed DCs were able to induce the appropriate T cells, indicating that the self-adjuvanting effects could occur in the absence of free lipopeptide interacting with additional TLR2-bearing cells in vivo. This study defines a hierarchy of lipopeptide constructs that can program DC to prime memory CD8(+) T cells that on recall function to clear influenza virus from the infected lung.
Lau
Yuk Fai
YF
Cooperative Research Centre for Vaccine Technology, Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.
Deliyannis
Georgia
G
Zeng
Weiguang
W
Mansell
Ashley
A
Jackson
David C
DC
Brown
Lorena E
LE
D000595:Amino Acid Sequence; D000818:Animals; D032701:Biomimetics; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007114:Immunization; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000472:pathogenicity; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008074:Lipoproteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D007252:Influenza Vaccines; D008074:Lipoproteins; D010455:Peptides