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The Context of Epitope Presentation Can Influence Functional Quality of Recalled Influenza A Virus-Specific Memory CD8⁺ T Cells¹

Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia

Lipopeptide constructs offer a novel strategy for eliciting effective cellular and humoral immunity by directly targeting the vaccine Ag to dendritic cells. Importantly, it is not known how closely immunity generated after lipopeptide vaccination mimics that generated after natural infection. We have used a novel lipopeptide vaccine strategy to analyze both the quantity and quality of CD8⁺ T cell immunity to an influenza A virus epitope derived from the acidic polymerase protein (PA₂₂₄) in B6 mice. Vaccination with the PA₂₂₄ lipopeptide resulted in accelerated viral clearance after subsequent influenza virus infection. The lipopeptide was also effective at recalling secondary D^bPA₂₂₄ responses in the lung. Lipopeptide recalled D^bPA₂₂₄-specific CTL produced lower levels of IFN- and TNF-, but produced similar levels of IL-2 when compared with D^bPA₂₂₄-specific CTL recalled after virus infection. Furthermore, lipopeptide- and virus-recalled CTL demonstrated similar TCR avidity. Interestingly, lipopeptide administration resulted in expansion of D^bPA₂₂₄-specific CTL using a normally subdominant TCRBV gene segment. Overall, these results demonstrate that protective CTL responses elicited by lipopeptide vaccines can be correlated with TCR avidity, IL-2 production, and broad TCR repertoire diversity. Furthermore, factors that impact the quality of immunity are discussed. These factors are important considerations when evaluating the efficacy of novel vaccine strategies that target dendritic cells for eliciting cellular immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an Australian National Health and Medical Research Council (NHMRC) Dora Lush Postgraduate Scholarship awarded to E.B.D., an NHMRC Burnet Fellowship awarded to P.C.D., an NHMRC R. D. Wright Fellowship awarded to S.J.T. and K.K., and Science Technology Innovation funds from the Government of Victoria, Australia.

² K.K. and S.J.T. contributed equally.

³ Address correspondence and reprint requests to Dr. Stephen J. Turner, Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail address: sjturn{at}unimelb.edu.au

⁴ Abbreviations used in this paper: MHCI, MHC class I; DC, dendritic cell; Pam2Cys, S-[2,3-bis(palmitoyloxy)propyl]cysteine; i.n., intranasal; MFI, mean fluorescence intensity.

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