TLR9-independent CD8+ T Cell Responses in Hepatic AAV Gene Transfer Through IL-1R1-MyD88 Signaling.

Upon viral infection of the liver, CD8+ T cell responses may be triggered despite the immune suppressive properties that manifest in this organ. We sought to identify pathways that activate responses to a neoantigen expressed in hepatocytes, using adeno-associated viral (AAV) gene transfer. It was previously established that cooperation between plasmacytoid dendritic cells (pDCs), which sense AAV genomes by Toll -like receptor 9 (TLR9), and conventional DCs promotes cross-priming of capsid-specific CD8+ T cells. Surprisingly, we find local initiation of a CD8+ T cell response against antigen expressed in X20% of murine hepatocytes, independent of TLR9 or type I interferons and instead relying on IL -1 receptor 1-MyD88 signaling. Both IL -1a and IL -1b contribute to this response, which can be blunted by IL -1 blockade. Upon AAV administration, IL-1-producing pDCs infiltrate the liver and co-cluster with XCR1+ DCs, CD8+ T cells, and Kupffer cells. Analogous events were observed following coagulation factor VIII gene transfer in hemophilia A mice. Therefore, pDCs have alternative means of promoting anti-viral T cell responses and participate in intrahepatic immune cell networks similar to those that form in lymphoid organs. Combined TLR9 and IL -1 blockade may broadly prevent CD8+ T responses against AAV capsid and transgene product.