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Shutdown of immunological priming and presentation after in vivo administration of adenovirus

Gene Therapy volume 19, pages 1095–1100 (2012)Cite this article

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Abstract

Adenoviral (Adv) vectors are widely used in both experimental and clinical trials for vaccination and gene therapy. Recombinant Adv can evoke potent innate immune responses and adaptive immune responses to encoded antigens. However, how Adv infection affects the response to subsequently encountered antigens is poorly understood. We show that intravenously administered replication defective (E1 and E3 deleted) Adv educes functional changes in dendritic cells (DC) resulting in impaired priming of cytotoxic T lymphocytes (CTL) more than 7 days after Adv treatment. Generalized DC activation was indicated by transient upregulation of CD86 and reduced endocytosis of fluorescent beads. It is known that CD8+ DC are predominantly responsible for uptake and presentation (cross-presentation) of exogenous antigens to CD8+ CTL. Hence, impaired endocytosis in CD8+, but not CD8−, DC at 7 days after Adv administration provided an explanation for the impaired CTL response to antigen at this time. Shutdown of cross-presentation was confirmed using cytochrome c (cytc), an agent that selectively depletes cross-presenting DC. Adv-infection rendered CD8+ DC resistant to depletion by cytc. As the cross-presentation pathway underlies CD8 T-cell responses to many cancers and to vaccines or viruses that do not directly infect DC, systemic Adv administration may impair these responses.

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Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia, Juvenile Diabetes Research Foundation and Diabetes Australia Research Trust. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. We are grateful to Nicole Ashman for technical assistance with mice.

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Author notes

  1. S L Londrigan

    Present address: 3Current address: Department of Microbiology and Immunology, The University of Melbourne, Parkville 3010, Victoria, Australia.,

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    R M Sutherland, S L Londrigan, J L Brady, H Azher, E M Carrington, Y Zhan, J Vega-Ramos, J A Villadangos & A M Lew

  2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia

    R M Sutherland, H Azher, E M Carrington, Y Zhan, J A Villadangos & A M Lew

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  1. R M Sutherland
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Correspondence to R M Sutherland.

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Sutherland, R., Londrigan, S., Brady, J. et al. Shutdown of immunological priming and presentation after in vivo administration of adenovirus. Gene Ther 19, 1095–1100 (2012). https://doi.org/10.1038/gt.2011.187

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