CD40 ligand-dependent activation of cytotoxic T lymphocytes by adeno-associated virus vectors in vivo: role of immature dendritic cells

J Virol. 2000 Sep;74(17):8003-10. doi: 10.1128/jvi.74.17.8003-8010.2000.


Recombinant adeno-associated virus type 2 (rAAV) is being explored as a vector for gene therapy because of its broad host range, good safety profile, and persistent transgene expression in vivo. However, accumulating evidence indicates that administration of AAV vector may initiate a detectable cellular and humoral immune response to its transduced neo-antigen in vivo. To elucidate the cellular basis of the AAV-mediated immune response, C57BL/6 mouse bone marrow-derived immature and mature dendritic cells (DCs) were infected with AAV encoding beta-galactosidase (AAV-lacZ) and adoptively transferred into mice that had received an intramuscular injection of AAV-lacZ 10 days earlier. Unexpectedly, C57BL/6 mice but not CD40 ligand-deficient (CD40L(-/-)) mice adoptively transferred with AAV-lacZ-infected immature DCs developed a beta-galactosidase-specific cytotoxic T-lymphocyte (CTL) response that markedly diminished AAV-lacZ-transduced gene expression in muscle fibers. In contrast, adoptive transfer of AAV-lacZ-infected mature DCs failed to elicit a similar CTL response in vivo. Our findings indicate, for the first time, that immature DCs may be able to elicit a CD40L-dependent T-cell immunity to markedly diminish AAV-lacZ transduced gene expression in vivo when a sufficient number of DCs capturing rAAV vector and/or its transduced gene products is recruited.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Bone Marrow Cells / cytology
  • CD40 Antigens / immunology*
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Dependovirus / genetics*
  • Dependovirus / immunology
  • Fluorescent Antibody Technique
  • Gene Transfer Techniques
  • Genetic Vectors
  • Lac Operon
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism


  • CD40 Antigens
  • Ligands
  • beta-Galactosidase