| First Author | Kumar SRP | Year | 2024 |
| Journal | Mol Ther | Volume | 32 |
| Issue | 2 | Pages | 325-339 |
| PubMed ID | 38053332 | Mgi Jnum | J:348863 |
| Mgi Id | MGI:7645556 | Doi | 10.1016/j.ymthe.2023.11.029 |
| Citation | Kumar SRP, et al. (2024) TLR9-independent CD8(+) T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling. Mol Ther 32(2):325-339 |
| abstractText | 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 approximately 20% of murine hepatocytes, independent of TLR9 or type I interferons and instead relying on IL-1 receptor 1-MyD88 signaling. Both IL-1alpha and IL-1beta 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. |
