title: CD8 T-cell priming upon mRNA vaccination is restricted to bone-marrow-derived antigen-presenting cells and may involve antigen transfer from myocytes.
abstract: Self-amplifying mRNAs (SAM(®) ) are a novel class of nucleic acid vaccines, delivered by a non-viral delivery system. They are effective at eliciting potent and protective immune responses and are being developed as a platform technology with potential to be used for a broad range of targets. However, their mechanism of action has not been fully elucidated. To date, no evidence of in vivo transduction of professional antigen-presenting cells (APCs) by SAM vector has been reported, while the antigen expression has been shown to occur mostly in the muscle fibres. Here we show that bone-marrow-derived APCs rather than muscle cells are responsible for induction of MHC class-I restricted CD8 T cells in vivo, but direct transfection of APCs by SAM vectors is not required. Based on all our in vivo and in vitro data we propose that upon SAM vaccination the antigen is expressed within muscle cells and then transferred to APCs, suggesting cross-priming as the prevalent mechanism for priming the CD8 T-cell response by SAM vaccines.
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lazzaro
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giovani
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Mangiavacchi
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Magini
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Maione
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Baudner
authors.affiliation: GSK Vaccines, Cambridge, MA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Geall
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.affiliation: Novartis Vaccines and Diagnostics s.r.l (a GSK Company), Siena, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Buonsanti
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000821:virology; D001854:Bone Marrow Cells / Q000276:immunology* / Q000821:virology; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002450:Cell Communication; D002460:Cell Line; D006224:Cricetinae; D045142:Cross-Priming; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology*; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000276:immunology* / Q000821:virology; D019590:Nucleocapsid Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D018183:Transplantation Chimera; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D007252:Influenza Vaccines; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins
keywords: antigen-presenting cells; cross-presentation; muscle cells; nucleic-acid-based vaccines; self-amplifying mRNA