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UBC Theses and Dissertations

The Ly-49 family of natural killer cell receptors Brennan, John A.


This thesis investigates the nature of receptors involved in target cell recognition by natural killer (NK) cells. N K cells are thought to scan for self class I major histocompatibility complex (MHC) antigens, receive negative signals from interactions with these molecules, and lyse those cells which are unable to deliver protective signals. This system ensures that cells which have extinguished expression of class I M H C and evade T cell immunity are detected by N K cells. Ly- 49A was the first N K cell receptor found to receive inhibitory signals from class I MHC on opposing cells. Because Ly-49A is expressed by a subset of N K cells and recognizes only a fraction of class I molecules, additional subsets of N K cells are thought to exist which express receptors for class I molecules not recognized by Ly- 49A. Ly-49A is a type II transmembrane protein belonging to a group of related molecules encoded by a murine multigene family. The expression patterns and functional activities of other members of the Ly-49 gene family was the topic of this thesis. Ly-49A and Ly-49C expression was shown to identify distinct single positive, double positive, and double negative subsets of N K cells. Both Ly-49A and Ly-49C were found to mediate adhesion to class I MHC on a variety of cell lines. The specificity of these receptors was shown to be distinct but overlapping, with Ly-49C having a much broader range of class I ligands. All members of the Ly-49 family have an extracellular region homologous to the carbohydrate recognition domain of C-type lectins. The functional relevance of this domain was demonstrated by the inhibition of Ly-49C-mediated cell adhesion by both exogenous polysaccharides as well as by the modification of target cell surface carbohydrates. This suggests that the glycosylation of class I MHC may be a critical element in Ly-49 recognition. These combined results support the hypothesis that Ly-49 is a family of N K cell receptors with related, but distinct functions. Ly-49A and Ly-49C are both expressed by NK cells, but not by the same NK cells, and they both bind to class I MHC molecules, but not the same class I molecules. These receptors may therefore be responsible for the generation of an NK cell repertoire capable of recognizing cells which lose expression of single class I molecules.

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