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Permanent link (DOI): https://doi.org/10.7939/R31N7XZ22

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Regulation of the inhibitory receptor LIR-1 in human natural killer cells Open Access

Descriptions

Other title
Subject/Keyword
Natural Killer Cells
LIR-1
Inhibitory Receptor
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Li, Nicholas L
Supervisor and department
Burshtyn, Deborah (Medical Microbiology and Immunology)
Examining committee member and department
Flood, Patrick (Dentistry)
Makrigiannis, Andrew (Biochemistry, Microbiology, and Immunology)
Anderson, Colin (Surgery)
Elliott, John (Medical Microbiology and Immunology)
Department
Department of Medical Microbiology and Immunology
Specialization

Date accepted
2013-09-26T14:19:32Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Natural killer (NK) cells are innate immune lymphocytes that provide protection against virus infection and transformation. The cytolytic activity of NK cells is controlled by the signaling of receptors that stimulate or inhibit activation. One such inhibitory receptor expressed on human NK cells is leukocyte Ig-like receptor (LIR) 1. LIR-1 is an Ig superfamily receptor with broad specificity for MHC-I and high affinity for the viral MHC-I homologue UL18 encoded by human cytomegalovirus (HCMV). Through the work presented in this thesis we investigated the mechanisms which regulate LIR-1 expression and function. The extent of LIR-1 expression on NK cells is quite variable between donors. We examined expression profiles of LIR-1 in 11 donors over 1 year to assess the stability of expression. Four donors demonstrated substantial increases in LIR-1⁺ NK cells, and high levels or changes in LIR-1 were not correlated with prior HCMV exposure. We found that cytokine stimulation enhances LIR-1 expression on mature NK cells and drives LIR-1 expression on immature NK cells. Together these results show LIR-1 on NK cells is under the control of select cytokines and suggest their availability may alter the NK repertoire in vivo. To investigate mechanisms that regulate LIR-1 function, we examined the receptor-ligand interaction, specifically on the NK cell membrane. LIR-1 can inhibit NK cells through the engagement of MHC-I expressed on a target cell (in trans) but the nature and the effects of LIR-1 interactions with MHC-I in cis are not well understood. We found the cis interaction alters recognition by only one of two antibodies known to block the interaction of LIR-1 with ligands expressed on target cells. Furthermore, disruption of LIR-1 cis interactions with MHC-I significantly enhanced UL18-Fc binding to NK92 cells and enhanced the relative inhibition of NK92 cells by HLA-G. These results have implications for LIR-1 function in scenarios such as infection when MHC-I levels on effector cells may be increased by cytokines such as interferons. In all these studies have revealed that LIR-1 is controlled by a variety of mechanisms, including those at the level of expression and at the cell surface by regulation of its availability for ligands.
Language
English
DOI
doi:10.7939/R31N7XZ22
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Davidson CL, Li NL, and Burshtyn DN. 2010. LILRB1 polymorphism and surface phenotypes of natural killer cells. Hum Immunol. Oct;71(10):942-9.Li NL, Davidson CL, Humar A, and Burshtyn DN. 2011. Modulation of the inhibitory receptor leukocyte Ig-like receptor 1 on human natural killer cells. Front. Immun. 2:46. DOI: 10.3389/fimmu.2011.00046.Li NL, Fu L, Uchtenhagen H, Achour A, Burshtyn DN. 2013. Cis association of leukocyte Ig-like receptor 1 with MHC-I modulates accessibility to antibodies and HCMV UL18. Eur. J. Immunol. 43:1042-1052. doi: 10.1002/eji.201242607.

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