title: Intrinsic transgene immunogenicity gears CD8(+) T-cell priming after rAAV-mediated muscle gene transfer.
abstract: Antitransgene CD8(+) T-cell responses are an important hurdle after recombinant adeno-associated virus (rAAV) vector-mediated gene transfer. Indeed, depending on the mutational genotype of the host, transgene amino-acid sequences of foreign origin can elicit deleterious cellular and humoral responses. We compared here two different major histocompatibility complex (MHC) class I epitopes of an engineered ovalbumin transgene delivered in muscle tissue by rAAV1 vector and found very different strength of CD8 responses, muscle destruction being correlated with the course of the immunodominant response. We further demonstrate that robust CD8(+) T-cell priming can occur through the cross-presentation pathway but requires the presence of either a strong MHC class II epitope or antibodies to the transgene product. Finally, manipulating transgene subcellular localization, we found that provided we avoid transgene expression in antigen presenting cells, the poorly accessible cytosolic form of ovalbumin transgene lacking strong MHC II epitope, evades CD8(+) T-cell priming and remains permanently expressed in muscle with no immune cell infiltration. Our results demonstrate that the intrinsic immunogenicity of transgenes delivered with rAAV vector in muscle can be manipulated in a rational manner to avoid adverse immune responses.
authors.affiliation: INSERM U1151, Institut Necker Enfants Malades, CNRS, UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Carpentier
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, Myology Research Center, UM76 and INSERM U974 and CNRS FRE 3617 and Institut de Myologie, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lorain
authors.affiliation: INSERM U1151, Institut Necker Enfants Malades, CNRS, UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chappert
authors.affiliation: INSERM U1151, Institut Necker Enfants Malades, CNRS, UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lalfer
authors.affiliation: INSERM U905, Université de Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Hardet
authors.affiliation: INSERM U1151, Institut Necker Enfants Malades, CNRS, UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Urbain
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, Myology Research Center, UM76 and INSERM U974 and CNRS FRE 3617 and Institut de Myologie, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Peccate
authors.affiliation: INSERM U905, Université de Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
authors.affiliation: UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
authors.affiliation: INSERM U1151, Institut Necker Enfants Malades, CNRS, UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Davoust
authors.affiliation: INSERM U1151, Institut Necker Enfants Malades, CNRS, UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Gross
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics*; D000939:Epitopes / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes
chemical_list: D000939:Epitopes