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Mol Ther. 2017 Apr 5;25(4):880-891. doi: 10.1016/j.ymthe.2017.02.014. Epub 2017 Mar 9.

The Balance between CD8+ T Cell-Mediated Clearance of AAV-Encoded Antigen in the Liver and Tolerance Is Dependent on the Vector Dose.

Author information

1
Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
2
Division of Immunology, Harvard Medical Center, Boston, MA 02115, USA.
3
Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, USA.
4
Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA. Electronic address: rherzog@ufl.edu.

Abstract

The liver continuously receives antigens from circulation and the gastrointestinal tract. A complex immune regulatory system has evolved in order to both limit inflammation and promote tolerance in the liver. Although in situ immune tolerance mechanisms enable successful gene therapy and liver transplantation, at the same time they facilitate chronic infections by pathogens such as hepatitis viruses. It is, however, poorly understood why hepatocytes infected with hepatitis viruses or transduced with adeno-associated virus (AAV)-based vectors may be rejected by CD8+ T cells several months later. We found that hepatic transfer of limited doses of an AAV-ovalbumin vector rapidly induced antigen-specific CD8+ T cells that only became functionally competent after >2 months. At this time, CD8+ T cells had downregulated negative checkpoint markers, e.g., the programmed death 1 [PD-1] receptor, and upregulated expression of relevant cytokines. At further reduced vector dose, only intrahepatic rather than systemic CD8+ T cell responses occurred, showing identical delay in antigen clearance. In contrast, PD-1-deficient mice rapidly cleared ovalbumin. Interestingly, higher vector dose directed sustained transgene expression without CD8+ T cell responses. Regulatory T cells, IL-10 expression, and Fas-L contributed to high-dose tolerance. Thus, viral vector doses profoundly impact CD8+ T cell responses.

KEYWORDS:

CD8(+) T cell; adeno-associated virus; gene therapy; hepatitis; liver; tolerance

PMID:
28284982
PMCID:
PMC5383644
DOI:
10.1016/j.ymthe.2017.02.014
[Indexed for MEDLINE]
Free PMC Article

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