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    Allelic Variation in KIR2DL3 Generates a KIR2DL2-like Receptor with Increased Binding to its HLA-C Ligand

    Cover for Allelic Variation in KIR2DL3 Generates a KIR2DL2-like Receptor with Increased Binding to its HLA-C Ligand
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    View/Open: Frazier_georgetown_0076D_12385.pdf (4.1MB) Bookview

    Creator
    Frazier, William Robinson
    Advisor
    Hurley, Carolyn K
    Abstract
    Although extensive homology exists between their extracellular domains, natural killer cell inhibitory receptors KIR2DL2*001 and KIR2DL3*001 have previously been shown to differ substantially in their HLA-C binding avidity. To explore the largely uncharacterized impact of allelic diversity, the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated for surface expression and binding affinity to their HLA-C group 1 and 2 ligands. Although no significant differences in the degree of cell membrane localization were detected in a transfected human NKL cell line by flow cytometry, surface plasmon resonance and KIR binding to a panel of HLA allotypes demonstrated that KIR2DL3*005 differed significantly from other KIR2DL3 allelic products in its ability to bind HLA-C. The increased affinity and avidity of KIR2DL3*005 for its ligand was also demonstrated to have a larger impact on the inhibition of IFN-γ production by the human KHYG-1 NK cell line compared to KIR2DL3*001, a low affinity allelic product. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 in KIR2DL3*005 was critical to the observed phenotype. Although these residues are distal to the KIR/HLA-C interface, molecular modeling suggests that alteration in the interdomain hinge angle of KIR2DL3*005 towards that found in KIR2DL2*001, another strong receptor of the KIR2DL2/3 family, may be the cause of this increased affinity. The regain of inhibitory capacity by KIR2DL3*005 suggests that the rapidly evolving KIR locus may be responding to relatively recent selective pressures placed upon certain human populations.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/707458
    Date Published
    2013
    Subject
    Killer Immunoglobulin-like Receptor; KIR; Natural Killer Cell; NK Cell; Polymorphism; Surface Plasmon Resonance; Immunology; Oncology; Immunology; Oncology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    209 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility