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,
*
Rheumatology and
Experimental Medicine Units, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, Belgium; and
Ludwig Institute for Cancer Research, Brussels, Belgium
NK cell populations were derived from murine splenocytes stimulated
by IL-2, IL-15, or the combination of IL-12 and IL-18. Whereas NK cells
derived with the latter cytokines consisted of an homogeneous
population of NK cells (DX5+CD3-), those
derived with IL-2 or IL-15 belonged to two different populations,
namely NK cells (DX5+CD3-) and T-NK cells
(DX5+CD3+). Among NK cells, only those derived
with IL-12/IL-18 produced detectable levels of cytokines, namely
IFN-
, IL-10, and IL-13 (with the exception of IL-13 production by NK
cells derived with IL-2). As for T-NK cells, IL-2-stimulated cells
produced a wide range of cytokines, including IL-4, IL-5, IL-9, IL-10,
and IL-13, but no IFN-, whereas IL-15-derived T-NK cells failed to
produce any cytokine. Switch-culture experiments indicated that T-NK
cells derived in IL-2 and further stimulated with IL-12/IL-18 produced
IFN- and higher IL-13 levels. Next, we observed that NK/T-NK cell
populations exerted distinct effects on Ig production by autologous
splenocytes according to the cytokines with which they were derived.
Thus, addition of NK cells derived in IL-12/IL-18 inhibited Ig
production and induced strong cytotoxicity against splenocytes, whereas
addition of NK or T-NK cells grown in IL-2 or IL-15 did not.
Experiments performed in IFN-R knockout mice demonstrated that
IFN- was not involved in the killer activity of IL-12/IL-18-derived
NK cells. The hypothesis that their cytotoxic activity was related to
the induction of target apoptosis was confirmed on murine A20 lymphoma
cells. Experiments performed in MRL/lpr mice indicated
that IL-12/IL-18-derived NK cells displayed their distinct killer
activity through a Fas-independent pathway. Finally, perforin was much
more expressed in IL-12/IL-18-derived NK cells as compared with IL-2-
or IL-15-derived NK cells, an observation that might explain their
unique cytotoxicity.
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