The Chediak-Higashi gene in humans. III. Studies on the mechanisms of NK impairment.

Lymphocytes from six Chediak-Higashi (CH) patients were markedly depressed in their ability to lyse tumour cell targets in both 51Cr release and single cell cytotoxicity assays. The frequency of lymphocytes bearing the OKM1 marker and the frequency of T3+, T4+, T8+, Ia+, Mo1+, Mo2+ and B1+ cells was normal among sheep erythrocyte rosetting (E+) and non-rosetting (E-) peripheral blood leucocytes analysed by flow cytofluorography. Cells expressing the NK shared markers, OKM1, mac-1, FcR, and the characteristic large granular lymphocyte (LGL) morphology of NK cells were also present in normal numbers in the highly enriched NK fraction separated on Percoll density gradients. This fraction did not contain detectable numbers of cells expressing the Mo2 marker of human monocytes. Therefore most of the cells stained by monoclonal OKM1 and mac-1 in this fraction are likely NK cells, rather than monocytes, and we conclude that the size of the NK pool in CH patients is probably normal. The capacity of CH lymphocytes to recognize and bind to tumour cells was also normal as was the subsequent burst of oxygen intermediates produced by the NK cells in a chemiluminenscence assay. We have shown elsewhere that O2- generation is directly involved in activating subsequent steps in the NK cytolytic pathway. These results suggest that NK cells in CH patients are present in normal frequency but are blocked at some post-recognition, post-activation step in the cytolytic pathway subsequent to the burst of oxygen intermediates but preceding the lethal hit.