Inhibition of murine natural killer cell differentiation by dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a naturally occurring steroid. We have previously shown that dietary DHEA (0.45% wt/wt) inhibits murine lymphopoiesis but not myelopoiesis. To assess the effect of DHEA on stages of natural killer (NK) cell differentiation, lethally irradiated mice fed DHEA or not were infused with 10(6) or 20 x 10(6) syngeneic bone marrow cells (BMC) as a source of transplantable NK cell progenitors. The differentiation of progenitor cells to lytic NK cells was assessed by the ability to clear radiolabeled YAC-1 tumor cells from the lungs. DHEA-fed recipients of 10(6) or 20 x 10(6) BMC failed to generate NK activity. Because NK progenitor cells are believed to differentiate into interleukin-2 (IL-2)-responsive precursor cells before maturation, BMC from recipient mice were cultured with IL-2 and the generation of NK cells was assessed. DHEA feeding prevented the generation of IL-2-responsive precursor cells in recipients of 10(6) BMC, but this inhibition was overcome in recipients of 20 x 10(6) BMC. To evaluate the capacity of stem cells to generate NK progenitor cells in DHEA-fed mice, the ability of marrow cells from primary recipients to generate NK activity in irradiated secondary recipients was determined. The production of NK progenitors was inhibited 20-fold. Thus, DHEA appears to inhibit the generation of NK progenitors from more primitive stem cells, the differentiation of progenitors into IL-2-responsive precursors cells and the maturation of IL-2-responsive precursor cells into mature NK cells.