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Plasmacytoid and conventional dendritic cells cooperate in cross-priming AAV capsid-specific CD8+ T cells

Geoffrey L. Rogers, Jamie L. Shirley, Irene Zolotukhin, Sandeep R.P. Kumar, Alexandra Sherman, George Q. Perrin, Brad E. Hoffman, Arun Srivastava, Etiena Basner-Tschakarjan, Mark A. Wallet, Cox Terhorst, Moanaro Biswas and Roland W. Herzog

Key points

  • Cross-priming of AAV capsid-specific CD8+ T cells requires cooperation between distinct subsets of dendritic cells.

  • Innate immune sensing of the viral DNA genome induces cross-presentation of viral capsid in trans.

Abstract

Adeno-associated virus (AAV) is a replication-deficient parvovirus that is extensively used as a gene therapy vector. CD8+ T cell responses against the AAV capsid protein can, however, affect therapeutic efficacy. Little is known about the in vivo mechanism that leads to the cross-priming of CD8+ T cells against the input viral capsid antigen. Here we report that the TLR9-MyD88 pattern-recognition receptor pathway is uniquely capable of initiating this response. By contrast, the absence of TLR2, STING, or addition of TLR4 agonist has no effect. Surprisingly, both conventional (cDCs) and plasmacytoid dendritic cells (pDCs) are required for the cross-priming of capsid-specific CD8+ T cells, while other antigen presenting cells are not involved. TLR9 signaling is specifically essential in pDCs but not in cDCs, indicating that sensing of the viral genome by pDCs activates cDCs in trans to cross-present capsid antigen during CD8+ T cell activation. Cross-presentation and cross-priming depend not only on TLR9, but also on IFN I signaling, and both mechanisms can be inhibited by administering specific molecules to prevent induction of capsid-specific CD8+ T cells. Thus, these outcomes directly point to therapeutic interventions and demonstrate that innate immune blockade can eliminate unwanted immune responses in gene therapy.

  • Submitted November 14, 2016.
  • Accepted May 1, 2017.