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Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

Abstract : The pro-tolerogenic environment of the liver makes this tissue an ideal target for gene replacement strategies. In other peripheral tissues such as the skeletal muscle, anti-transgene immune response can result in partial or complete clearance of the transduced fibers. Here, we characterized liver-induced transgene tolerance after simultaneous transduction of liver and muscle. A clinically relevant transgene, α-sarcoglycan, mutated in limb-girdle muscular dystrophy type 2D, was fused with the SIINFEKL epitope (hSGCA-SIIN) and expressed with adeno-associated virus vectors (AAV-hSGCA-SIIN). Intramuscular delivery of AAV-hSGCA-SIIN resulted in a strong inflammatory response, which could be prevented and reversed by concomitant liver expression of the same antigen. Regulatory T cells and upregulation of checkpoint inhibitor receptors were required to establish and maintain liver-mediated peripheral tolerance. This study identifies the fundamental role of the synergy between Tregs and upregulation of checkpoint inhibitor receptors in the liver-mediated control of anti-transgene immunity triggered by muscle-directed gene transfer.
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https://hal.archives-ouvertes.fr/hal-02392771
Contributor : Jean Davoust <>
Submitted on : Tuesday, December 22, 2020 - 7:37:00 PM
Last modification on : Thursday, March 4, 2021 - 3:50:24 PM

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Jérôme Poupiot, Helena Costa Verdera, Romain Hardet, Pasqualina Colella, Fanny Collaud, et al.. Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle. Molecular Therapy - Methods and Clinical Development, Nature Publishing Group, 2019, 15, pp.83 - 100. ⟨10.1016/j.omtm.2019.08.012⟩. ⟨hal-02392771⟩

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