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

Jérôme Poupiot (1) , Helena Costa Verdera (1) , Romain Hardet (2) , Pasqualina Colella (1) , Fanny Collaud (1) , Laurent Bartolo (3) , Jean Davoust (3) , Peggy Sanatine (1) , Federico Mingozzi (2) , Isabelle Richard (1) , Giuseppe Ronzitti (1)

1 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
2 Centre de recherche en Myologie – U974 SU-INSERM
3 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades

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.

Mots clés: AAV; peripheral tolerance; gene transfert; liver; checkpoint inhibitors; Tregs; PD-1; LAG3

Domaines: Organisation et fonctions cellulaires [q-bio.SC]

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, 2019, 15, pp.83 - 100. ⟨10.1016/j.omtm.2019.08.012⟩. ⟨hal-02392771⟩