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

  • Author / Creator
    Li, Nicholas L
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Medical Microbiology and Immunology
  • Supervisor / co-supervisor and their department(s)
    • Burshtyn, Deborah (Medical Microbiology and Immunology)
  • Examining committee members and their departments
    • Anderson, Colin (Surgery)
    • Elliott, John (Medical Microbiology and Immunology)
    • Flood, Patrick (Dentistry)
    • Makrigiannis, Andrew (Biochemistry, Microbiology, and Immunology)