Date of Original Version
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.
Hui, D. J., Basner-Tschakarjan, E., Chen, Y., Davidson, R. J., Buchlis, G., Yazicioglu, M., Pien, G. C., Finn, J. D., Haurigot, V., Tai, A., Scott, D. W., Cousens, L. P., Shangzhen, Z., De Groot, A. S., & Mingozzi, F. (2013). Modulation of CD8+ T cell responses to AAV vectors with IgG-derived MHC class II epitopes. Molecular Therapy, 21(9), 1727-1737.
Available at: http://dx.doi.org/10.1038/mt.2013.166