Version 1
: Received: 1 August 2024 / Approved: 2 August 2024 / Online: 2 August 2024 (11:20:36 CEST)
How to cite:
Li, N.; Kumar, S. R.; Cao, D.; Munoz-Melero, M.; Arisa, S.; Brian, B. A.; Greenwood, C. M.; Yamada, K.; Duan, D.; Herzog, R. W. Redundancy in Innate Immune Pathways that Promote CD8+ T cell Responses in AAV Muscle Gene Transfer. Preprints2024, 2024080159. https://doi.org/10.20944/preprints202408.0159.v1
Li, N.; Kumar, S. R.; Cao, D.; Munoz-Melero, M.; Arisa, S.; Brian, B. A.; Greenwood, C. M.; Yamada, K.; Duan, D.; Herzog, R. W. Redundancy in Innate Immune Pathways that Promote CD8+ T cell Responses in AAV Muscle Gene Transfer. Preprints 2024, 2024080159. https://doi.org/10.20944/preprints202408.0159.v1
Li, N.; Kumar, S. R.; Cao, D.; Munoz-Melero, M.; Arisa, S.; Brian, B. A.; Greenwood, C. M.; Yamada, K.; Duan, D.; Herzog, R. W. Redundancy in Innate Immune Pathways that Promote CD8+ T cell Responses in AAV Muscle Gene Transfer. Preprints2024, 2024080159. https://doi.org/10.20944/preprints202408.0159.v1
APA Style
Li, N., Kumar, S. R., Cao, D., Munoz-Melero, M., Arisa, S., Brian, B. A., Greenwood, C. M., Yamada, K., Duan, D., & Herzog, R. W. (2024). Redundancy in Innate Immune Pathways that Promote CD8+ T cell Responses in AAV Muscle Gene Transfer. Preprints. https://doi.org/10.20944/preprints202408.0159.v1
Chicago/Turabian Style
Li, N., Dongsheng Duan and Roland W. Herzog. 2024 "Redundancy in Innate Immune Pathways that Promote CD8+ T cell Responses in AAV Muscle Gene Transfer" Preprints. https://doi.org/10.20944/preprints202408.0159.v1
Abstract
While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T cell responses against the transgene product upon vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1>MyD88 and TLR9>MyD88>IFN I>IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. We further provide evidence that CpG depletion of vector genomes and inclusion of TLR9 inhibitory sequences can have a synergistic effect. However, even low-frequency CD8+ T cell responses could eliminate transgene expression. Thus, innate immune avoidance/blockade strategies, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of redundancy of immune activating pathways.
Keywords
adeno-associated virus; CD8 T cell; TLR9; IL-1; muscle
Subject
Biology and Life Sciences, Virology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
