Unlicensed’ natural killer cells dominate the response to cytomegalovirus infection

Natural killer (NK) cells expressing inhibitory receptors that bind to self-MHC class I are “licensed ” or rendered functionally more responsive to stimulation, whereas “unlicensed ” NK cells lacking receptors for self-MHC class I are hyporesponsive. Here we show that, contrary to the licensing hypothesis, unlicensed NK cells were the primary mediators of NK cell-mediated control of mouse cytomegalovirus infection in vivo. Depletion of unlicensed, but not licensed, NK cells impaired control of viral titers. Transfer of unlicensed NK cells was more protective than licensed NK cells. SHP-1 signaling limited proliferation of licensed, but not unlicensed NK cells during infection. Thus, “unlicensed ” NK cells are critical for protection against viral infection. Natural killer (NK) cells mediate resistance to certain viral infections and play an important role in the rejection of some tumors1. NK cells possess an extensive repertoire of activating and inhibitory receptors, many of which are expressed in a stochastic fashion resulting in subsets of NK cells defined by their receptor expression2. Several families of NK cell receptors, such as activating Killer cell Immunoglobulin-like Receptors (KIR) in humans, activating Ly49 receptors in rodents, NKG2D, the natural cytotoxicity receptors (NKp30