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Investigating the role of the D0 domain of KIR3DL1 in ligand interaction and exploring the effect of LILRB1 on KIR3DL1 signaling Open Access


Other title
ligand interaction
Type of item
Degree grantor
University of Alberta
Author or creator
Fu, Li
Supervisor and department
Burshtyn, Debroah (Medical Microbiology and Immunology)
Examining committee member and department
Margulies, David (laboratory of Immunology, National Institute of Allergy and Infectious Diseases)
Hemmings, Denise (Obstetrics & Gynecology)
Hazes, Bart (Medical Microbiology and Immunology)
Kane, Kevin (Medical Microbiology and Immunology)
Department of Medical Microbiology and Immunology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Natural killer (NK) cells are crucial in early defense against viral infections by rapidly terminating infected cells and by secreting cytokines to shape adaptive immune responses. The activity of NK cells is regulated by balance of activating and inhibitory signals during interaction with target cells. Inhibitory receptors are important as they trigger inhibitory signals to prevent damage of normal health tissue through interaction with self MHC-I molecules. KIR3DL1 is one of inhibitory receptors implicated in resistance to viral diseases such as HIV/AIDS. Structurally, KIR3DL1 contains three Ig domains and has specificity for MHC-I molecules belonging to the HLA-Bw4 serogroup. The receptor’s second (D1) and third (D2) Ig domains confer the Bw4 specificity, but the role of the first Ig domain (D0) in ligand recognition remained enigmatic until recently. In this thesis, I found that KIR3DL1 expressed in YTS cells and as a soluble receptor can weakly recognize additional MHC-I molecules including HLA-B*0702 and HLA-G. This interaction is highly sensitive to blocking with antibodies to the MHC-I a3-domain and the anti-KIR3DL1-D0 antibody, Z27, but not the canonical blocking antibody DX9. Using chimeric receptors between KIR3DL1 and KIR2DL1 expressed on YTS cells and as soluble Fc-fusion proteins, I showed that the presence of a second and independent site of interaction between the KIR3DL1-D0 domain and MHC-I proteins. This data is consistent with the finding of the D0 domain interaction with the MHC-I α1 region in the co-crystal structure reported by Vivian JP et al in 2012. However, after reconciling antibody blocking results with the published co-crystal structure, I proposed a new model in which a third site of interaction occurs. Moreover, using same strategies, I showed KIR3DL1 binding to xenogenic MHC-I, such as mouse MHC-I. Similarly as shown in HLA, either anti-α3 antibodies or Z27 dramatically inhibited the binding. In addition, mutagenesis studies showed that position 194 at the α3 domain somehow interferes KIR3DL1 binding with unknown mechanism. Collectively, the results may shed light on how KIRs evolved, and be used to interpret genetic association of KIR with diseases such as HIV/AIDS.
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.
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