HLA-C REVISITED - 10 YEARS OF CHANGE

During the past 10 years knowledge about the interactions between majo r histocompatibility complex (MHC) class I molecules and the T-cell re ceptor (TCR) complex of cytotoxic T-cells (CTL) has developed dramatic ally. But the primary interest, both with respect to structure as well as function, has concentrated on HLA-A and -B molecules because of th eir high sequence polymorphism and their dominating presence at the ce ll surface. In contrast, HLA-C molecules seemed to be of only minor im portance in the cascade of immune reactions owing to their more limite d polymorphism and reduced levels of surface expression. The inability to define a number of antigen specificities had the result that HLA-C molecules were often neglected in studies of immune response, transpl antation, and disease association. More recently a new function has be en identified for HLA class I molecules where they act as inhibitors o f the lytic capacity of natural killer (NK) cells and non-MHC-restrict ed T-cells. Moreover, the understanding of this novel mode of negative regulation of cytotoxicity was remarkably influenced by HLA-C since t hese were the first HLA class I molecules found to have such inhibitor y potential. With this new inhibitory function serving as an essential component of the immune system, HLA-C molecules can no longer be negl ected.