1. TLR9-independent CD8 + T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling.
- Author
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Kumar SRP, Biswas M, Cao D, Arisa S, Muñoz-Melero M, Lam AK, Piñeros AR, Kapur R, Kaisho T, Kaufman RJ, Xiao W, Shayakhmetov DM, Terhorst C, de Jong YP, and Herzog RW
- Subjects
- Animals, Mice, Capsid Proteins, Dendritic Cells, Interleukin-1 metabolism, Liver metabolism, Toll-Like Receptor 9 genetics, Toll-Like Receptor 9 metabolism, CD8-Positive T-Lymphocytes, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism
- 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., Competing Interests: Declaration of interests R.W.H. is serving on scientific advisory boards for Regeneron Pharmaceuticals-Intellia Therapeutics collaboration, Prevail Therapeutics, Pfizer, and Biomarin, and is also receiving funding from Roche (for an unrelated gene therapy project)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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