Fig. 1.

Mechanisms of NK cell memory formation. During MCMV infection, naive NK cells that express the activating receptor Ly49H recognize the virally encoded glycoprotein m157 on the surface of MCMV-infected host cells, resulting in the robust activation and proliferation of antigen-specific NK cells. This process is critically dependent on proinflammatory IL-12 signaling through STAT4 and Zbtb32, and costimulatory signaling through the activating receptor DNAM-1. During clonal proliferation, antigen-specific NK cells maintain viability by increasing the expression of miR155 to antagonize the prodeath factors Noxa and SOCS1; however, at the peak of virus-driven expansion, effector NK cells undergo BIM-mediated cell death to form a stable pool of long-lived memory NK cells in a process that depends on endogenous IL-15. MCMV-elicited memory NK cells can respond robustly to a secondary challenge with MCMV but are less responsive to heterologous infection.