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Cover for Allelic Variation in KIR2DL3 Generates a KIR2DL2-like Receptor with Increased Binding to its HLA-C Ligand
dc.contributor.advisorHurley, Carolyn Ken
dc.creatoren
dc.date.accessioned2014-01-10T15:34:36Zen
dc.date.available2014-01-10T15:34:36Zen
dc.date.created2013en
dc.date.issueden
dc.date.submitted01/01/2013en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_707458.tar;APT-ETAG: 75a6dafe0ed4079dfc2631fc0e5ac601; APT-DATE: 2017-01-30_11:44:23en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractAlthough 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.en
dc.formatPDFen
dc.format.extent209 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceTumor Biologyen
dc.subjectKiller Immunoglobulin-like Receptoren
dc.subjectKIRen
dc.subjectNatural Killer Cellen
dc.subjectNK Cellen
dc.subjectPolymorphismen
dc.subjectSurface Plasmon Resonanceen
dc.subject.lcshImmunologyen
dc.subject.lcshOncologyen
dc.subject.otherImmunologyen
dc.subject.otherOncologyen
dc.titleAllelic Variation in KIR2DL3 Generates a KIR2DL2-like Receptor with Increased Binding to its HLA-C Liganden
dc.typethesisen


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