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

Authors
  • Shirley, Jamie L1
  • Keeler, Geoffrey D1
  • Sherman, Alexandra1
  • Zolotukhin, Irene1
  • Markusic, David M2
  • Hoffman, Brad E1
  • Morel, Laurence M3
  • Wallet, Mark A3
  • Terhorst, Cox4
  • Herzog, Roland W5
  • 1 Department Pediatrics, University of Florida, Gainesville, FL, USA.
  • 2 Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. , (India)
  • 3 Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
  • 4 Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA. , (Israel)
  • 5 Department Pediatrics, University of Florida, Gainesville, FL, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: [email protected] , (India)
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
Nov 15, 2019
Identifiers
DOI: 10.1016/j.ymthe.2019.11.011
PMID: 31780366
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Adeno-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. Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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