Mature resting Ly6Chigh natural killer cells can be reactivated by IL‐15

Mature NK cells are heterogeneous as to their expression levels of cell surface molecules. However, the functional differences and physiological roles of each NK-cell subset are not fully understood. In this study, we report that based on the Ly6C expression levels, mature C57BL/6 murine NK cells can be subdivided into Ly6Clow and Ly6Chigh subsets. Ly6Chigh NK cells are in an inert state as evidenced by the production of lower levels of IFN-γ and granzyme B, and they exhibit poorer proliferative potential than Ly6Clow NK cells. In addition, adoptive transfer experiments revealed that Ly6Chigh NK cells are derived from Ly6Clow NK cells in the steady state. These results strongly suggest that Ly6Chigh NK cells are resting cells in the steady state. However, in vitro, Ly6Chigh NK cells become Ly6Clow NK cells with strong effector functions upon stimulation with IL-15. Moreover, Ly6Chigh NK cells also revert to Ly6Clow NK cells in vivo upon injection of the IL-15 inducers polyI:C and CpG. Taken together, these results demonstrate the plasticity of mature NK cells and suggest that Ly6Chigh NK cells are a reservoir of potential NK cells that allow effective and strong response to infections.