title: Modulation of CD8+ T cell responses to AAV vectors with IgG-derived MHC class II epitopes.
abstract: Immune responses directed against viral capsid proteins constitute a main safety concern in the use of adeno-associated virus (AAV) as gene transfer vectors in humans. Pharmacological immunosuppression has been proposed as a solution to the problem; however, the approach suffers from several potential limitations. Using MHC class II epitopes initially identified within human IgG, named Tregitopes, we showed that it is possible to modulate CD8+ T cell responses to several viral antigens in vitro. We showed that incubation of peripheral blood mononuclear cells with these epitopes triggers proliferation of CD4+CD25+FoxP3+ T cells that suppress killing of target cells loaded with MHC class I antigens in an antigen-specific fashion, through a mechanism that seems to require cell-to-cell contact. Expression of a construct encoding for the AAV capsid structural protein fused to Tregitopes resulted in reduction of CD8+ T cell reactivity against the AAV capsid following immunization with an adenoviral vector expressing capsid. This was accompanied by an increase in frequency of CD4+CD25+FoxP3+ T cells in spleens and lower levels of inflammatory infiltrates in injected tissues. This proof-of-concept study demonstrates modulation of CD8+ T cell reactivity to an antigen using regulatory T cell epitopes is possible.
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Davidson
authors.forename: George
authors.initials: G
authors.lastname: Buchlis
authors.forename: Mustafa
authors.initials: M
authors.lastname: Yazicioglu
authors.forename: Gary C
authors.initials: GC
authors.lastname: Pien
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Finn
authors.forename: Virginia
authors.initials: V
authors.lastname: Haurigot
authors.forename: Alex
authors.initials: A
authors.lastname: Tai
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Leslie P
authors.initials: LP
authors.lastname: Cousens
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G