Previous work using wild-type mice, A/WSN challenge virus, and non-cloned DI WSN virus showed that there were MHC-restricted virus-specific CD8+ and CD4+ CTL responses in the lungs of H-2k mice infected Selleckchem NVP-BKM120 with A/WSN or A/WSN + inactivated DI virus. These mice all died. CTL responses were diminished in mice inoculated with A/WSN + DI virus and these all survived [19]. Analysis of the specificity of T cell responses using vaccinia viruses expressing individual influenza A virus proteins showed that, unusually for influenza A virus infections, the response in A/WSN-infected, DI virus-treated mice was largely strain specific. Depletion of both CD8+ and CD4+

cells with specific antibody was needed to abolish lung consolidation and for mice infected with A/WSN or A/WSN + inactivated DI virus to survive [19], but like the SCID mice reported here, infectious virus in the lung was not cleared. In contrast, when mice depleted of CD8+ and CD4+ cells were inoculated with A/WSN + DI virus, lung infectivity was cleared, presumably with the assistance of local, T cell-independent, GW3965 supplier virus-specific antibody. These mice produced a haemagglutinin (HA)-specific

antibody that was highly unusual as it was not neutralizing but, when adoptively transferred, protected naïve animals from A/WSN [20], [22] and [25]. The same HA-specific lung IgG conferred cell killing ability on naïve cells in a MHC class I restricted manner [23] In addition, a monoclonal antibody isolated from lung B cells possessed no haemagglutination-inhibition activity

but recognised HA on the surface Metalloexopeptidase of cells only in the context of the cognate MHC class I antigen, and in so doing mimicked the specificity of a T cell receptor [24]. Thus A/WSN + DI virus stimulated in the lung two highly unusual HA-specific antibodies. Mice infected with A/WSN or A/WSN + inactivated DI virus did not make the HA-specific, non-neutralizing lung antibody. HA-specific antibody from the serum of the same animals was conventionally neutralizing, but evidently did not enter the lung compartment. In summary, there are some unusual and possibly unique interactions between the immune system and DI virus when it is replicated in mice. Broadly it appears that the immunomodulatory activity of influenza A virus is modified by DI virus through its interfering property to produce a generally favourable outcome for the host animal [21]. Whether or not different influenza A DI RNA sequences modulate immune responses in the same way remains to be determined. Analysis of RNA taken at day 16 from the lungs of sick SCID mice that had received active 244 DI virus + A/WSN showed that the sequence, and thus the properties, of the 244 RNA had not changed. Infectious A/WSN isolated from the same group of mice was also unchanged in sensitivity to interference by 244 DI virus in subsequent tests in immune competent mice in vivo.