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

Authors

Daniel J. Hui
Etiena Banser-Tschakarjan
Yifeng Chen
Robert J. Davidson
George Buchlis
Mustafa Yazicioglu
Gary C. Pien
Jonathan D. Finn
Virginia Haurigot
Alex Tai
David W. Scott
Leslie P. Cousens
Shangzhen Zhou
Anne S. De Groot, University of Rhode IslandFollow
Federico Mingozzi

Document Type

Article

Date of Original Version

2013

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.

Citation/Publisher Attribution

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