HLA-Specific and Non-HLA-Specific Human NK Receptors

Abstract

Unlike cytolytic T cells, which recognize and kill target cells expressing MHC molecules, NK lymphocytes can efficiently lyse target cells that lack the expression of one or more MHC class I molecules. Presumably, this allows the immune system to detect and kill certain types of tumor or virus-infected cells trying to evade T cell recognition by downregulating one or more class I molecules (Garrido et al. 1995; Ikeda et al. 1997). Based on the above observation, the cytolytic activity mediated by NK cells was originally viewed as non-MHC-restricted (Kiessling et al. 1975; Herberman et al. 1975; Trinchieri 1989). Although it is likely that triggering receptor(s) involved in the induction of NK-cell-mediated cytotoxicity are indeed represented by structures that recognize non-MHC ligands, the importance of MHC molecules in controlling NK functions is now well-established. Thus, it was shown that NK cells have the ability to kill “normal nonself” cells while sparing “normal self” cells expressing normal levels of MHC class I molecules and at least some allogeneic target cells expressing MHC class I molecules that are identical or related to the self ones (Karre 1992; Moretta et al. 1994; Moretta 1992). In humans, this is possible thanks to the expression, on NK cells, of a series of receptors that recognize HLA class I molecules (Moretta et al. 1996; Valiante et al. 1997). Some of these, by delivering inhibitory signals to the NK cells, avoid eliminating normal self cells. Other HLA class-I-specific receptors exist that induce NK cell triggering and might be involved in the elimination of allogeneic cells or autologous cells expressing “abnormal” HLA molecules.