Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18

We investigated the effects of IL-12 and IL-18 on unstimulated murine splenocytes and observed that the two cytokines strongly synergized for their proliferation, whereas IL-12 and IL-18 alone were essentially inactive in this respect. Phenotypical and functional analyses of cells proliferating in response to IL-12 and IL-18 revealed that large granular Ly-49C(+) DX5(+) CD3(-) NK blasts mere expanded in these cultures and that they displayed cytotoxic activity against Yac-l cells, a murine NK cell target. Further analyses indicated three major differences between NK cells appearing in response to IL-12 and IL-18 and those derived in the presence of other NK cell growth factors, such as IL-2 or IL-15, First, a population of T-NK cells, i.e. expressing T cell (TCR alpha beta, CD3) and NK cell. (Ly-49) markers, was detected amongst cells growing in IL-2 or IL-15 but not in cultures supplemented with IL-12 and IL-18. Second, most NK cells derived with IL-2 or IL-15 expressed the NK1.1 antigen, while those derived with IL-12 and IL-18 did not. Finally, striking differences were observed regarding cytokine production, Cells stimulated with IL-12 and IL-18 in combination, but not with IL-2 or IL-15, produced IFN-gamma, IL-3, IL-6 and TNF. lFN-gamma was not involved in the response of NK cells to IL-12 and IL-18, as indicated by experiments demonstrating that: the combination of the two cytokines displayed similar effects on spleen cells from IFN-gamma R-knock-out mice. Receptor (IL-12R beta 1, IL-12R beta 2 and IL-18R) gene expression studies did not indicate that the mechanism underlying the synergy between IL-12 and IL-18 involved reciprocal induction of their receptors. Taken together, our results demonstrate that IL-12 and IL-18 exert striking synergistic activities for NK cell proliferation and activation, distinct from those induced by IL-2 or IL-15. (C) 1999 Academie Press.