Variation in adenovirus transgene expression between BALB/c and C57BL/6 mice is associated with differences in interleukin-12 and gamma interferon production and NK cell activation

The innate immune response against replication-defective adenoviruses (Ad) is poorly defined. We and others have previously observed striking differen ces in the rate at which the Ad vector itself or the virus encoding a varie ty of transgenes is eliminated in different mouse strains. Here, we report that Ad infection of BALB/ mice is associated,vith sixfold-higher levels of serum alanine aminotransferase and that Ad transgenes induce two- to three fold-higher levels of intrahepatic NK cells and NK activity compared to C57 BL/6 mice. The increase in NK activation in BALB/c mice was associated with similar to4-fold higher level of mRNA expression of a newly described NKG2 receptor activator, H-60, as well as increased expression of interleukin-1 2 and gamma interferon mRNAs in BALB/c mice compared to C57BL/6 mice. NK de pletion in BALB/c mice or defective NK function in C3H beige mice extended transgene expression compared to their appropriate controls, and attenuatio n of NK together with CD8 T-cell function had a synergistic effect. These f indings indicate that there are intrinsic differences in the innate immune responses of different mouse strains to Ad and Ad transgenes and that NK ce lls, in cooperation with CD8 T cells, play a pivotal role in the early exti nction of transgene expression in BALB/c mice.