CD8+ T cell activation occurs 24 hours after AAV administration and is driven by muscle promoter specificity
Abstract
Immune responses against transgene products can compromise adeno-associated virus-mediated (AAV-mediated) gene transfer. Although several factors influencing this immunogenicity have been described, the early in vivo events driving CD8+ T cell activation remain poorly defined. Here, we examined antigen presentation kinetics following intramuscular AAV administration in mice. Strikingly, viral genomes were detected in draining lymph nodes as early as 1 hour after injection, and transgene-derived peptides were presented to CD8+ T cells from day 1, resulting in progressive activation and first cell divisions detected at day 4. Removal of the injection site demonstrated that AAV particles reaching draining lymph nodes within the first hour were sufficient to induce cytotoxic transgene-specific CD8+ T cells. Finally, AAV vectors incorporating different muscle-specific promoters and regulatory sequences were evaluated. Although muscle specific, all promoters exhibited variable transgene expression in dendritic cells in vitro, correlating with early T cell activation in vivo; notably, those associated with higher early antigen presentation induced robust T cell response, whereas reduced presentation correlated with absence of CD8+ T cells. These findings reveal an unexpectedly early onset of transgene-derived epitope presentation, modulated by promoter specificity, which critically shapes CD8+ T cell response. This provides a rationale for evaluating and mitigating AAV immunogenicity in gene therapy design.
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BibTeX
@article{jeanpierre2026cell,
title = {{CD8+ T cell activation occurs 24 hours after AAV administration and is driven by muscle promoter specificity}},
author = {Lindsay Jeanpierre and Coralie Pecquet and Hanadi Saliba and Pauline Finard and Stéphane Terry and Gianni Tavella and Inès Guesmia and Sylvie Boutin and Bérangère Bertin and Sofia Benkhelifa-Ziyyat and Giuseppe Ronzitti and David-Alexandre Gross},
journal = {JCI Insight},
year = {2026},
month = jun,
doi = {10.1172/jci.insight.202541},
url = {https://hal.science/hal-05769988v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - CD8+ T cell activation occurs 24 hours after AAV administration and is driven by muscle promoter specificity
AU - Lindsay Jeanpierre
AU - Coralie Pecquet
AU - Hanadi Saliba
AU - Pauline Finard
AU - Stéphane Terry
AU - Gianni Tavella
AU - Inès Guesmia
AU - Sylvie Boutin
AU - Bérangère Bertin
AU - Sofia Benkhelifa-Ziyyat
AU - Giuseppe Ronzitti
AU - David-Alexandre Gross
PY - 2026
DA - 2026/06/09
JO - JCI Insight
DO - 10.1172/jci.insight.202541
UR - https://hal.science/hal-05769988v1
AB - Immune responses against transgene products can compromise adeno-associated virus-mediated (AAV-mediated) gene transfer. Although several factors influencing this immunogenicity have been described, the early in vivo events driving CD8+ T cell activation remain poorly defined. Here, we examined antigen presentation kinetics following intramuscular AAV administration in mice. Strikingly, viral genomes were detected in draining lymph nodes as early as 1 hour after injection, and transgene-derived peptides were presented to CD8+ T cells from day 1, resulting in progressive activation and first cell divisions detected at day 4. Removal of the injection site demonstrated that AAV particles reaching draining lymph nodes within the first hour were sufficient to induce cytotoxic transgene-specific CD8+ T cells. Finally, AAV vectors incorporating different muscle-specific promoters and regulatory sequences were evaluated. Although muscle specific, all promoters exhibited variable transgene expression in dendritic cells in vitro, correlating with early T cell activation in vivo; notably, those associated with higher early antigen presentation induced robust T cell response, whereas reduced presentation correlated with absence of CD8+ T cells. These findings reveal an unexpectedly early onset of transgene-derived epitope presentation, modulated by promoter specificity, which critically shapes CD8+ T cell response. This provides a rationale for evaluating and mitigating AAV immunogenicity in gene therapy design.
SN - 2379-3708
ER -