Turnover and Proliferation of NK Cells in Steady State and Lymphopenic Conditions

To gain insight into NK cell dynamics, we investigated the turnover and proliferation rates of NK cells in normal and lymphopenic conditions. In contrast to previous reports suggesting a very rapid turnover of NK cells, continuous 5-bromo-2'-deoxyuridine (BrdU)-labeling studies demonstrated that the time necessary for labeling 50% of splenic NK cells in mature mice was 17 days, similar to the rate of labeling of memory T cells. In contrast, in young mice, splenic NK cells labeled very rapidly with BrdU, although cell cycle analyses and BrdU pulse-labeling studies suggested that most of this proliferation occurred in a precursor population. A somewhat larger percentage of bone marrow NK cells was cycling, suggesting that these proliferating cells are the precursors of the mostly nondividing or slowly dividing splenic NK cells. Splenic NK cells from mature mice also did not proliferate significantly when transferred to normal mice, but did proliferate when transferred to irradiated mice. Thus, NK cells, like T cells, undergo homeostatic proliferation in a lymphopenic environment. Homeostatic proliferation of NK cells was not dependent on host cell class I molecules or host production of IL-15. Nevertheless, the number of recovered NK cells was much lower in IL-15(-/-) hosts. These results suggest that IL-15 is not essential for homeostatic proliferation of NK cells, but is necessary for survival of the NK cells. Our results provide important basic information concerning the production and replacement of NK cells.