NK cells make up a cell family defined by an index of direct effector functions of being cytotoxic to transformed cells. Recently, NK cells have attracted attention for the possibility of having effects on the development of adaptive immunity through the modification of DC maturation, activation, and cell death (Gerosa et al., 2002). We have been conducting in vitro experiments on how NK cells are involved in DC maturation and activation (Jinushi et al., 2006). DCs that are inductively differentiated from peripheral blood monocytes of healthy donors using GM-CSF and IL-4 show an immature phenotype (IM-DC). In order to clarify how NK cells might be involved in the maturation of these IM-DCs, we conducted a mixed-culture test of IM-DCs and NK cells. The co-culture of IM-DCs with NK cells did not induce maturation, but a 48-hour co-culture of IM-DCs with hepatoma cell lines and NK cells led to increased expression of CD40, CD86, and HLA-DR in DCs and induced DC maturation. During the co-culture, we inserted a trans-well membrane between DCs and NK cells, but DC maturation was induced. This showed that DC maturation was induced via humoral factors, and not by direct cell-to-cell contacts. In fact, the stimulation of IM-DCs using a 24-hour mixed-culture supernatant of NK cells and hepatoma cells resulted in inducing maturation. This maturation was accompanied by functional activation, and allostimulatory capacity toward CD4-positive T cells from healthy donors was significantly enhanced compared with that of IM-DC.
Next, we examined DC maturation and functional activation resulting from co-culture with hepatoma cells and NK cells using NK cells from patients with HCV instead of those from healthy donors. The stimulation of IM-DCs using the supernatant of a 24-hour co-culture of NK cells from HCV patients with hepatoma cells resulted in suppressed DC maturation and allostimulatory capacity compared with the case in which we used NK cells from healthy donors. In order to examine whether NKG2A signals from HLA-E during a mixed culture of hepatoma cells and NK cells are involved in this inhibition of DC maturation and activation, we conducted an inhibition experiment by adding anti-NKG2A antibody during the mixed culture. DC maturation and activation resulting from culture supernatant stimulation were enhanced by adding anti-NKG2A antibody either in the case of
NK cells from healthy donors or in the case of those from patients with HCV. However, DC maturation and activation were more notably enhanced when NK cells from patients with HCV were used. Levels of various cytokines present in the culture supernatant were quantitatively analyzed in each case, and the levels of IFNy and TNFa were high when NK cells from healthy donors were used, whereas the levels of IL-10 and TGF0 were high when those from patients with HCV were used. Results from experiments where a neutralizing antibody was added for each cytokine into the culture supernatant suggested that the change of the cytokine balance affected DC maturation and activation.
These observations suggest that in patients with HCV, excess NKG2A signals in NK cells not only have an inhibitory effect on the direct effector activity of NK cells but also have a negative effect on the subsequent DC maturation and activation. With improved methods to detect specific T cell responses, such as the ELISPOT assay, there have been reports of some T cell responses specific to cancer antigens in the case of HCC as well. Down-regulated adaptive immune responses from NK cells to DCs might inhibit development of the adaptive immunity.
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