The Resolution Phase of NK Cell Proliferation and IFNgamma Production Following Viral Infection Are Highly Regulated Processes

In response to MCMV infection, NK cells undergo three distinct phases of proliferation: the non-specific phase mediated by pro-proliferative cytokines; the specific phase mediated by recognition of an MCMV-encoded protein by an NK cell activating receptor, Ly49H; and the resolution phase, whose mechanism is unknown. MCMV infection of RAG mice, which lack all adaptive immune cells, results in prolonged proliferation of NK cells despite similar viral titers compared to wildtype mice. Interestingly, there are different kinetics for Ly49H+ and Ly49H- NK cells. We have identified several additional markers that may distinguish NK cells that have been specifically activated through their receptor from those non-specifically activated by cytokines. Using mice that lack only one or two adaptive lymphocyte populations, we determined that alphabeta and gammadelta T cells have a redundant ability to resolve NK cell proliferation. An adoptive transfer system was developed to further probe the characteristics of T cells required for this process. Finally, we have observed a significant decrease in NK cell numbers coincident with the resolution of various NK cell effector functions (IFNgamma production and proliferation), which suggests a role for apoptosis in the resolution of NK cell activation. The resolution of IFNgamma production is associated with increased formation of active caspase 8, which appears to be dependent on signaling through TRAIL-R.