Differentiating intercellular interactions that induce cytotoxic activity and cytokine release by NK cells

Abstract

Tumor cells are able to induce activation in NK cells, represented by cytotoxicity and cytokine production. Recent studies suggest that the induction of these two functions of the NK cells have different requirements. This study investigates the hypothesis that the ability of tumor cells to induce cytokine production and/or cytotoxicity in NK cells depends on the expression of particular combinations of receptors on NK cells and ligands on the tumor cells. Resting NK cells from five healthy donors, with distinct NK receptor repertoires, were activated by tumor cell lines and their ability to kill the tumor cells and to secrete IFNgamma was evaluated. The tumor cell lines, represented by four myeloma cell lines and Daudi, K562 and Jurkat, were evaluated for their expression of several NK receptor activating ligands, (ULBPs, MICA/B, PRR2, CD48, HLA-E and HLA-G) inhibitory ligands, (MHC class I molecules), and adhesion molecules, (CD54, CD58, CD56 and CD45). Each tumor cell line expressed a particular combination of these ligands. Resting NK cells cocultured with the tumor cell lines were activated, thus able to kill the tumor cells and/or to secrete IFNgamma. The induction of IFNgamma-secreting NK cells in the resting NK population after exposure to tumor cell lines was positively correlated with the expression of the activating ligands ULBPs, PRR2, HLA-E and HLA-G and negatively correlated with the presence of HLA-C2 molecules. The coexpression of CD58 and CD54 along with ULBPs was suggested to be involved in induction of IFNgamma secretion in resting NK cells. Resting NK cells were also able to kill the tumor cells, including the myeloma cell lines, through NKG2D-MICA/B interaction and Fas/FasL pathways. The coexpression of CD45 along with MICA/B had a positive effect on cytotoxicity, but CD56 was a negative regulator of tumor cell lysis. In conclusion, the results suggest that the initiation of the two main functions of NK cells might be a result the interaction of distinct combinations of NK receptors and ligands and adhesion molecules expressed by tumor cells.