Engagement of MHC class I proteins on natural killer cells inhibits their killing capacity

We have studied whether engagement of MHC class I (MHC-I) molecules on natural killer (NK) cells can influence the NK killing activity. Human NK effector cells, enriched by nylon wool passage, were incubated with monoclonal antibodies (MoAb) to MHC-I followed by cross-linking with secondary rabbit anti mouse Ig or streptavidin. Cross linking of MHC-I molecules on NK cells resulted in a clear inhibition of the NK activity against the target cells K562, Molt-4 and U937. The inhibitory effect was selective for MHC-I and was not seen with MoAb to MHC-II or CD56 molecules. The inhibition was not mediated via Fc receptors since F(ab)2 fragments of the MHC-I MoAb W6/32 were as effective as the intact antibody. The best inhibition of NK activity was obtained using biotin-labelled F(ab)2 fragments of W6/32 and streptavidin as a cross-linker, where up to 70% reduction in NK cell activity was observed. Antibody dependent cellular cytotoxicity (ADCC) was also inhibited by cross-linking MHC-I molecules on the effector cells. The results show that antibody mediated cross-linking of MHC-I proteins on NK cells can inhibit their killing capacity. This indicates that MHC-I molecules on NK cells can be involved in the regulation of NK cytotoxicity, perhaps by transmitting inhibitory signals into the NK cell.