Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells

dc.contributor.authorShirley, Jamie L.
dc.contributor.authorKeeler, Geoffrey D.
dc.contributor.authorSherman, Alexandra
dc.contributor.authorZolotukhin, Irene
dc.contributor.authorMarkusic, David M.
dc.contributor.authorHoffman, Brad E.
dc.contributor.authorMorel, Laurence M.
dc.contributor.authorWallet, Mark A.
dc.contributor.authorTerhorst, Cox
dc.contributor.authorHerzog, Roland W.
dc.contributor.departmentPediatrics, School of Medicineen_US
dc.date.accessioned2020-01-31T19:53:21Z
dc.date.available2020-01-31T19:53:21Z
dc.date.issued2019
dc.description.abstractAdeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses employ antigen presentation by conventional dendritic cells (cDCs), which leads to cross-priming of capsid-specific CD8+ T cells. In this study, we sought to determine the mechanisms that promote licensing of cDCs, which is requisite for CD8+ T cell activation. Blockage of type 1 interferon (T1 IFN) signaling by monoclonal antibody therapy prevented cross-priming. Furthermore, experiments in cell-type-restricted knockout mice showed a specific requirement for the receptor for T1 IFN (IFNaR) in cDCs. In contrast, natural killer (NK) cells are not needed, indicating a direct rather than indirect effect of T1 IFN on cDCs. In addition, co-stimulation by CD4+ T cells via CD40-CD40L was required for cross-priming, and blockage of co-stimulation but not of T1 IFN additionally reduced antibody formation against capsid. These mechanistic insights inform the development of targeted immune interventions.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationShirley, J. L., Keeler, G. D., Sherman, A., Zolotukhin, I., Markusic, D. M., Hoffman, B. E., … Herzog, R. W. (2019). Type I Interferon Sensing by Conventional Dendritic Cells and CD4+ T Help are both Requisite for Cross-priming of AAV Capsid-specific CD8+ T Cells. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2019.11.011en_US
dc.identifier.urihttps://hdl.handle.net/1805/21966
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.ymthe.2019.11.011en_US
dc.relation.journalMolecular Therapyen_US
dc.rightsPublisher Policyen_US
dc.sourcePublisheren_US
dc.subjectadeno-associated virusen_US
dc.subjectinnate immunityen_US
dc.subjectCD8+ T cellen_US
dc.titleType I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cellsen_US
dc.typeArticleen_US
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