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

Daniel J. Hui, Etiena Basner-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, Federico Mingozzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish
Pages (from-to)1727-1737
Number of pages11
JournalMolecular Therapy
Volume21
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

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