International Immunology Advance Access originally published online on October 31, 2006
International Immunology 2006 18(12):1801-1813; doi:10.1093/intimm/dxl114
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Lipid-containing mimetics of natural triggers of innate immunity as CTL-inducing influenza vaccines
1 Cooperative Research Centre for Vaccine Technology, Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia
2 VacTX Pty. Ltd, Level 1, 123 Camberwell Road, Hawthorn East, Victoria 3123, Australia
3 Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Victoria 3165, Australia
Correspondence to: L. E. Brown; E-mail: lorena{at}unimelb.edu.au.
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-
-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.
Keywords: dendritic cells, lipids, lung, peptide, Toll-like receptors, virus
* These authors are the co-senior authors.
Transmitting editor: D. Tarlinton
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