Modulation of CD8+ T cell responses to AAV vectors with IgG-derived MHC class II epitopes

• Published in: Molecular therapy Vol. 21; no. 9; pp. 1727 - 1737
• Main Authors: Hui, Daniel J, Basner-Tschakarjan, Etiena, Chen, Yifeng, Davidson, Robert J, Buchlis, George, Yazicioglu, Mustafa, Pien, Gary C, Finn, Jonathan D, Haurigot, Virginia, Tai, Alex, Scott, David W, Cousens, Leslie P, Zhou, Shangzhen, De Groot, Anne S, Mingozzi, Federico
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2013; Elsevier Limited; Cell Press; Nature Publishing Group
• Subjects: Animals; Antigens; Antigens, Viral - genetics; Antigens, Viral - immunology; Capsid - immunology; Capsid Proteins - genetics; Capsid Proteins - immunology; Capsid Proteins - metabolism; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell cycle; Cells, Cultured; Clinical trials; Dependovirus - genetics; Dependovirus - immunology; Enzymes; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Epitopes, T-Lymphocyte - metabolism; Genetic Therapy; Genetic Vectors; Genomes; Hemophilia; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class II - immunology; Humans; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Life Sciences; Liver; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Original; Peptides; Spleen - immunology; T-Lymphocytes, Regulatory - immunology; Viruses; United States > US; Pennsylvania
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1038/mt.2013.166

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.