TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling
Sandeep Kumar, Moanaro Biswas, Di Cao, Sreevani Arisa, Maite Muñoz-Melero, Anh K. Lam, Annie R. Piñeros, Reuben Kapur, Tsuneyasu Kaisho, Randal J. Kaufman, Weidong Xiao, Dmitry M. Shayakhmetov, Cox Terhorst, Ype P. de Jong, Roland W. Herzog
Abstract
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 ∼20% of murine hepatocytes, independent of TLR9 or type I interferons and instead relying on IL-1 receptor 1-MyD88 signaling. Both IL-1α and IL-1β 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.