Natural killer cells destroy various tumor cells, virus infected cells and cells that express depressed or foreign MHC class I molecules, and may play a significant role in defense against transformed cells as well as infectious diseases. A great deal of evidence indicates that MHC class I molecules participate in recognition events by NK cells. Specifically, expression on target cells of class I molecules inhibits NK mediated lysis. The effect is specific for different class I molecules as shown by in vivo experiments where NK cells reject allogeneic or parental hematopoietic cell transplants, as well as by in vitro experiments, where clone or IL2 grown NK cells discriminate cells based on their MHC haplotype. Inhibition of NK cells by MHC molecules may indicate that NK cells function to destroy variant autologous cells that lose expression of one or more class I molecule. Alternatively, recognition of class I molecules by NK cells may be disrupted by binding of viral peptides to the class I molecules, resulting in destruction of virus infected cells. Recent studies implicate a family of linked NK cell surface receptors, which are type II integral membrane proteins and are distributed on NK subsets, as inhibitory receptors involved in NK recognition of class I molecules. How these receptors recognize Class I molecules is poorly understood, but several experiments indicate that the peptide binding groove of the class I molecule is involved in recognition. Another poorly understood issue is whether and how NK cell subsets which have the potential to lyse cells of a given MCH type are prevented from doing so in mice of that MHC type. Studies suggest that NK cells are self-tolerant, but the phenomenon has been difficult to address in in vitro systems, and the mechanism is not understood.
Our specific aims are three-fold. (1) to use cell lines deficient for putative peptide transporters to probe the role of peptides bound to class I molecules in inhibition of NK cells. (2) To produce a soluble version of one of the putative NK receptors for class I in order to probe the binding specificity of these receptors (3) To determine whether specific NK cells are truly self tolerant by employing new mouse strains and transgenic mice expressing a given NK receptor for class I on all of its NK cells, and to employ chimeric mice to distinguish models of tolerance induction.
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