“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.