The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice.
Recombinant adeno-associated viruses (AAVs) have been used widely for in vivo gene therapy. However, adaptive immune responses to AAV have posed a significant hurdle in clinical application of AAV vectors. Recent advances have suggested a crucial role for innate immunity in shaping adaptive immune responses. How AAV activates innate immunity, and thereby promotes AAV-targeted adaptive immune responses, remains unknown. Here we show that AAV activates mouse plasmacytoid DCs (pDCs) via TLR9 to produce type I IFNs. In vivo, the TLR9-MyD88 pathway was crucial to the activation of CD8+ T cell responses to both the transgene product and the AAV capsid, leading to loss of transgene expression and the generation of transgene product-specific and AAV-neutralizing antibodies. We further demonstrate that TLR9-dependent activation of adaptive immunity targeting AAV was mediated by type I IFNs and that human pDCs could be activated in vitro to induce type I IFN production via TLR9. These results reveal an essential role for the TLR9-MyD88-type I IFN pathway in induction of adaptive immune responses to AAV and suggest that strategies that interfere with this pathway may improve the outcome of AAV-mediated gene therapy in humans.
Zhu
Jiangao
J
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Huang
Xiaopei
X
Yang
Yiping
Y
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D019076:Transgenes
D007370:Interferon Type I; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9