Decline in natural killer cell-mediated immunosurveillance in aging mice--a consequence of reduced cell production and tumor binding capacity.

The mechanism(s) responsible for the functional deficiencies in aging mice of natural killer (NK) cells, the lymphocytes active in early neoplasia development, are unknown. The aim of the present study was to examine the effect of indomethacin, a prostaglandin synthetase inhibitor, and recombinant interleukin-2 (rIL-2), an NK cell stimulant, on the NK cell numbers and function of aging mice. This combination is highly effective in inducing proliferation and activation of the NK cells in young adult mice. Ten- to 13-month-old DBA/2 mice received either indomethacin daily for 9 days in their drinking water, or rIL-2 twice a day for 4 days, or both agents combined. Untreated aging mice had 50% fewer splenic NK cells than did young adult (5-8 weeks) DBA/2 mice, although bone marrow contained NK cell numbers similar to that of young adult mice. Neither indomethacin alone, rIL-2 alone nor the combination of both could induce an increase in NK cell numbers or function in aging mice. Radioautography combined with immunoperoxidase labelling techniques revealed that the production of new NK cells from the bone marrow of aging mice was significantly reduced relative to that of young adult mice. This was reflected in low numbers of newly formed NK cells accumulating in the spleens of aging mice. The target binding capacity, a necessary precytolytic event, of aging mouse NK cells was also reduced compared to that of young adult mice. The results suggest that the functional deficiencies of aging mouse NK cells are a consequence of multiple factors including an absolute loss of NK cells resulting from a reduced production of such cells in the bone marrow and a decreased capacity of NK cells to bind their tumor targets.