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Tetramer-Based Enrichment of Preexisting Anti-AAV8 CD8 + T Cells in Human Donors Allows the Detection of a T EMRA Subpopulation

Abstract : Pre-existing immunity to AAV capsid may compromise the safety and efficiency of rAAV-mediated gene transfer in patients. Anti-capsid cytotoxic immune responses have proven to be a challenge to characterize because of the scarcity of circulating AAV-specific CD8 + T lymphocytes which can seldom be detected with conventional flow cytometry or ELISpot assays. Here, we used fluorescent MHC class I tetramers combined with magnetic enrichment to detect and phenotype AAV8-specific CD8 + T cells in human PBMCs without prior amplification. We showed that all healthy individuals tested carried a pool of AAV8-specific CD8 + T cells with a CD45RA + CCR7 − terminally-differentiated effector memory cell (T EMRA) fraction. Ex vivo frequencies of total AAV-specific CD8 + T cells were not predictive of IFNγ ELISpot responses but interestingly we evidenced a correlation between the proportion of T EMRA cells and IFNγ ELISpot positive responses. T EMRA cells may then play a role in recombinant AAV-mediated cytotoxicity in patients with preexisting immunity. Overall, our results encourage the development of new methods combining increased detection sensitivity of AAV-specific T cells and their poly-functional assessment to better characterize and monitor AAV capsid-specific cellular immune responses in the perspective of rAAV-mediated clinical trials.
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Submitted on : Tuesday, January 21, 2020 - 2:31:33 PM
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Celine Vandamme, Rebecca Xicluna, Leslie Hesnard, Marie Devaux, Nicolas Jaulin, et al.. Tetramer-Based Enrichment of Preexisting Anti-AAV8 CD8 + T Cells in Human Donors Allows the Detection of a T EMRA Subpopulation. Frontiers in Immunology, Frontiers, 2020, 10, pp.3110. ⟨10.3389/fimmu.2019.03110⟩. ⟨inserm-02447186⟩



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