Interleukin-12-activated natural killer cells recognize B7 costimulatory molecules on tumor cells and autologous dendritic cells.

Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1- and B7-2-expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12-activated NK cells secreted higher levels of interferon-gamma, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2-activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12-activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12-activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.