Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8+ T cells
| Autor: | Brad E. Hoffman, George Q. Perrin, Sandeep R. P. Kumar, Geoffrey L. Rogers, Mark A. Wallet, Jamie L. Shirley, Etiena Basner-Tschakarjan, Arun Srivastava, Irene Zolotukhin, Moanaro Biswas, Roland W. Herzog, Alexandra Sherman, Cox Terhorst |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
viruses Plasma Cells Immunology chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Biology Lymphocyte Activation Biochemistry Mice 03 medical and health sciences Immune system Antigen medicine Animals Cytotoxic T cell Mice Knockout Innate immune system TLR9 hemic and immune systems Dendritic Cells Genetic Therapy Gene Therapy Cell Biology Hematology biochemical phenomena metabolism and nutrition Dependovirus Virology Cell biology TLR2 030104 developmental biology Toll-Like Receptor 9 Myeloid Differentiation Factor 88 Capsid Proteins Interferon type I CD8 medicine.drug |
| Zdroj: | Blood. 129:3184-3195 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2016-11-751040 |
| Popis: | 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 crosspriming of CD8+ T cells against the input viral capsid antigen. In this study, we report that the Toll-like receptor 9 (TLR9)-MyD88 pattern-recognition receptor pathway is uniquely capable of initiating this response. By contrast, the absence of TLR2, STING, or the addition of TLR4 agonist has no effect. Surprisingly, both conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are required for the crosspriming of capsid-specific CD8+ T cells, whereas 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 crosspriming depend not only on TLR9, but also on interferon type 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. |
| Databáze: | OpenAIRE |
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