Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Clara Lawler, Cindy S. E. Tan, J. Pedro Simas, Philip G. Stevenson

Gamma-herpesviruses establish persistent, systemic infections and cause cancers. Murid Herpesvirus-4 (MuHV-4) provides a unique window onto the early events of host colonization. It spreads via lymph nodes. While dendritic cells (DC) pass MuHV-4 to lymph node B cells, subcapsular sinus macrophages (SSM), which capture virions from the afferent lymph, restrict its spread. Understanding how this restriction works offers potential clues to a more comprehensive defence. Type I interferons (IFN-I) blocked SSM lytic infection and reduced lytic cycle-independent viral reporter gene expression. Plasmacytoid DC were not required; but neither were SSM the only source of IFN-I, as IFN-I blockade increased infection in both intact and SSM-depleted mice. NK cells restricted lytic SSM infection independently of IFN-I, and SSM-derived virions spread to the spleen only when IFN-I responses and NK cells were both lacking. Thus, multiple innate defences allowed SSM to adsorb virions from the afferent lymph with relative impunity. Enhancing IFN-I and NK cell recruitment could potentially also restrict DC infection and so improve infection control. Human gamma-herpesviruses cause cancers by infecting B cells. However vaccines designed to block virus binding to B cells have not stopped infection. Using a related gamma-herpesvirus of mice, we showed that B cells are infected not via cell-free virus but via infected myeloid cells. This suggests a different strategy to stop B cell infection: stop virus production by myeloid cells. Not all myeloid infection is productive. We show that subcapsular sinus macrophages, which do not pass infection to B cells, restrict gamma-herpesvirus production by recruiting type 1 interferons and natural killer cells. Therefore a vaccine that speeds the recruitment of these defences might stop B cell infection.