Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526301
Title: A study of KIR binding to HLA-C
Author: Fadda, Lena
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Abstract:
NK cell cytotoxic functions are under the control of a large array of inhibitory and activating cell surface receptors. One class of inhibitory receptors are the MHC class I specific Killer Immunoglobulin-like Receptors (KIRs). Different KIRs recognise different groups of HLA molecules. KIR2DL2 and KIR2DL3 segregate as alleles of the same locus and recognise the same HLA-C group 1 allotypes (HLA-C1). Loss of an inhibitory signal is one mechanism by which NK cells might recognise an infected cell. KIR-Ig proteins were generated to study the direct binding of KIR2DL2 and KIR2DL3 to HLA-C1: peptide complexes. The TAP-deficient T2 cell line expresses HLA-Cw*0102 (HLA-C1) and can be loaded with exogenous peptide to generate stable peptide: MHC class I complexes. Using an endogenous peptide, VAPWNSLSL as a template, known to bind to HLA-Cw*0102, a panel of seven peptides with mutations at residues 7 and 8 was studied to assess KIR binding. A peptide hierarchy was defined for KIR2DL2 and KIR2DL3 binding; peptides that mediated strong, intermediate or weak recognition of KIR to HLA-Cw*0102 were identified. A similar peptide hierarchy was observed to inhibit NK cells in CD107a assays. We showed that KIR2DL3 binds more strongly to HLA-Cw*0102: peptide than KIR2DL2, although in CD107a assays, KIR2DL2+ NK cells were not more inhibited than KIR2DL3+ NK cells. The peptide hierarchy was used to generate in vitro peptide repertoires containing strong and weak KIR-binding peptides. We observed that the weak KIR-binding peptide VAPWNSDAL can abrogate the inhibition of NK cells by the strong KIR-binding peptide VAPWNSFAL, despite levels of HLA-C remaining constant. This loss of NK cell inhibition in the presence of VAPWNSDAL occurred at more than 1 log higher concentration of VAPWNSFAL than in the absence of VAPWNSDAL. These data indicate that changes in peptide repertoire are significantly more efficient than class I down-regulation at releasing NK cells from inhibition.
Supervisor: Khakoo, Salim Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.526301  DOI: Not available
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