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

Recombinant adeno-associated virus type 2 (rAAV) is being explored as a vec tor 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 cell ular and humoral immune response to its transduced neo-antigen in vivo. To elucidate the cellular basis of the AAV-mediated immune response, C57BL/6 m ouse bone marrow-derived immature and mature dendritic cells (DCs) were inf ected with AAV encoding beta-galactosidase (AAV-lacZ) and adoptively transf erred into mice that had received an intramuscular injection of AAV-lacZ 10 days earlier. Unexpectedly, C57BL/6 mice but not CD40 ligand-deficient (CD 40L(-/-)) mice adoptively transferred with AAV-lacZ-infected immature DCs d eveloped a beta-galactosidase-specific cytotoxic T-lymphocyte (CTL) respons e that markedly diminished AAV-lacZ-transduced gene expression in muscle fi bers. In contrast, adoptive transfer of AAV-lacZ-infected mature DCs failed to elicit a similar CTL response in vivo. Our findings indicate, for the f irst 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.