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

Abstract

NK cell activation is controlled by the integration of signals from cytokine receptors and germline encoded activation and inhibitory receptors. NK cells undergo two distinct phases of activation during MCMV infection: a nonselective phase mediated by pro-inflammatory cytokines and a specific phase driven by signaling through Ly49H, an NK cell activation receptor that recognizes infected cells. We sought to delineate cell surface markers that could distinguish NK cells that had been activated nonselectively from those that had been specifically activated through NK cell receptors. We demonstrated that Sca-1 is highly upregulated during viral infections (to an even greater extent than CD69) and serves as a novel marker of early, nonselective NK cell activation. Indeed, a greater proportion of Sca-1 NK cells produced IFN-γ compared to Sca-1 NK cells during MCMV infection. In contrast to the universal upregulation of Sca-1 (as well as KLRG1) on NK cells early during MCMV infection, differential expression of Sca-1, as well as CD27 and KLRG1, was observed on Ly49H and Ly49H NK cells late during MCMV infection. Persistently elevated levels of KLRG1 in the context of down