Enhancement of antigen-specific Natural Killer cell ‘memory’ by removal of a viral innate immune signalling inhibitor

Abstract

Abstract Previous analysis of the vaccinia virus (VACV) K7 protein showed that this protein has a Bcl-2 structure, inhibits the pathways leading to activation of IRF3 and NF-κB and contributes to virus virulence. Here we show that infection with a VACV lacking the K7 protein (vΔK7) induced weaker VACV-neutralising antibody responses 1 month post infection, but still provided better protection against intranasal challenge with VACV. This implied a role for cellular immunity. By transfer of NK cells or CD8+ T cells to recipient mice and subsequent challenge with VACV, it was demonstrated that the NK cells from mice infected with vΔK7 induced better protection against challenge, compared to NK cells derived from wild type immunised mice. In contrast, adoptive transfer of CD8+ T cells from mice immunised with either virus conferred equal protection. In recipient mice, the NK cells transferred from vΔK7-infected mice were more responsive to homologous virus challenge and showed enhanced migration to the site of infection. By staining donor cells with CFSE prior to adoptive transfer, it was seen that donor NK cells proliferated greater in response to VACV than influenza challenge, and NK cells from vΔK7-immunised mice enhanced this effect compared to NK cells from wild type immunised mice. This study shows that VACV-specific NK memory cells can confer protection against VACV challenge and that the production of these memory cells is enhanced by deletion of the VACV K7 protein.