Persistent gamma-herpesvirus infection induces a CD4 T cell response containing functionally distinct effector populations.

The direct effector mechanisms of CD4 T cells during gamma-herpesvirus 68 (gammaHV68)-persistent infection are less well understood than those of their CD8 T cell counterparts, although there is substantial evidence that CD4 T cells are critical for the control of persistent gamma-herpesvirus infection. Our results show that in gammaHV68-persistently infected mice, CD4 T cells are not cytokine polyfunctional, but there is a division of labor in the CD4 T cell compartment in which CD4 T cells polarize toward two distinct populations with different effector functions: IFN-gamma producers and CD107(+) cytolytic effectors. These two CD4 T cell effector populations degranulate and produce IFN-gamma during steady state without need for exogenous antigenic restimulation, which is fundamentally different from that observed with gammaHV68-specific CD8 T cells. By using anti-IFN-gamma Ab depletions and IFN-gamma-deficient mice, we show that CD4 T cell-mediated cytotoxicity in vivo is not dependent on IFN-gamma activity. In addition, our data show that purified CD4 T cells isolated from gammaHV68-latently infected mice have the capacity to inhibit gammaHV68 reactivation from latency. Our results support the concept that CD4 T cells are critical effectors for the control of gamma-herpesvirus latent infection, and they mediate this effect by two independent mechanisms: IFN-gamma production and cytotoxicity.