Cytolytic mechanisms involved in non-MHC-restricted cytotoxicity in Chediak-Higashi syndrome

To determine the mechanisms responsible for the impaired lymphocyte-mediate d cytotoxicity in Chediak-Higashi syndrome (CHS), we investigated the killi ng ability of peripheral blood lymphocytes (PBL) from three patients with C HS using several kinds of target cells that were sensitive to perforin, Fas ligand (FasL), and/or tumour necrosis factor-alpha (TNF-alpha). Freshly is olated CHS PBL did not kill K562 target cells, killing of which by normal P BL was perforin-dependent, as demonstrated by complete inhibition by concan amycin A (CMA), an inhibitor of perforin-based cytotoxicity. In contrast, t he CHS PBL exhibited substantial cytotoxicity against Jurkat cells, which w as only partially inhibited by CMA treatment but not by the addition of neu tralizing anti-Fast or anti-TNF-alpha antibodies. IL-2-activated CHS PBL ex hibited substantial levels of cytotoxicity against K562 and Jurkat cells, t he levels being 74% and 83% of the respective normal control values, respec tively. CMA treatment showed that while the cytotoxicity of IL-2-activated CHS PBL against K562 was largely dependent on perforin, that against Jurkat was largely not. IL-2-activated CHS PBL expressed Fast mRNA, and killed Fa s transfectants. These findings indicate that CHS PBL have an ability to ki ll some target cells via a perforin-mediated pathway, especially when they are activated by IL-2. It was also demonstrated that CHS PBL can exert cyto toxicity against certain target cells by utilizing Fast and an undefined ef fector molecule other than perforin, Fast, or TNF-alpha.