Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector–mediated gene therapy
- 15 January 2009
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 113 (3) , 538-545
- https://doi.org/10.1182/blood-2008-01-131375
Abstract
Recombinant adeno-associated virus (rAAV) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. Whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. Here we characterized CD8+ T-cell activity against β-galactosidase and enhanced green fluorescent protein, model antigens containing major histocompatibility complex (MHC) class I epitopes that are constitutively produced in murine skeletal muscle after rAAV vector transduction. Antigen-specific CD8+ T cells were detected in the spleen and liver of mice within 7 days of muscle transduction. CD8+ T-cell frequencies in these organs were stable, and effector functions were intact for months despite ongoing antigen production in muscle. CD8+ T cells also infiltrated transduced muscle, where frequencies were at least 5-fold higher than in untransduced spleen and liver. Significantly, the majority of antigen-specific CD8+ T cells in vector-transduced muscle were not functional. Loss of function in the muscle was associated with programmed death of the effector cells. Stable gene expression therefore depended on selective death of CD8+ T cells at the site of antigen production, an effective mechanism for subverting immunity that is also potentially reversible.Keywords
This publication has 56 references indexed in Scilit:
- Recombinant adeno-associated virus vectors induce functionally impaired transgene product–specific CD8+ T cells in miceJournal of Clinical Investigation, 2007
- Vaccines Based on Novel Adeno-Associated Virus Vectors Elicit Aberrant CD8+T-Cell Responses in MiceJournal of Virology, 2007
- A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophyJournal of Translational Medicine, 2007
- Adeno-Associated Virus Type 2 (AAV2) Capsid-Specific Cytotoxic T Lymphocytes Eliminate Only Vector-Transduced Cells Coexpressing the AAV2 Capsid In VivoJournal of Virology, 2007
- Life and death in peripheral T cellsNature Reviews Immunology, 2007
- Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infectionThe Journal of Experimental Medicine, 2007
- Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 ExpressionJournal of Virology, 2007
- Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infectionThe Journal of Experimental Medicine, 2006
- Treatment of human disease by adeno-associated viral gene transferHuman Genetics, 2006
- Transforming growth factor‐β promotes ‘death by neglect’ in post‐activated human T cellsImmunology, 2001