Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Hdl Handle:
http://hdl.handle.net/10034/606112
Title:
Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity
Authors:
O'Connor, Geraldine M.; Vivian, Julian P.; Widjaja, Jacqueline M.; Bridgeman, John S.; Gostick, Emma; Lafont, Bernard A.; Anderson, Stephen K.; Price, David A.; Brooks, Andrew G.; Rossjohn, Jamie; McVicar, Daniel W.
Abstract:
Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation.
Affiliation:
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; Non-Human Primate Immunogenetics and Cellular Immunology Unit, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Basic Science Program, Leidos Biomedical Research Inc., Laboratory of Experimental Immunology, Frederick National Laboratory, Frederick, MD 21702; Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Citation:
O’Connor, G. M., Vivian, J. P., Widjaja, J. M., Bridgeman, J. S., Gostick, E., Lafont, B. A. P., . . . McVicar, D. W. (2014). Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity. The Journal of Immunology. doi: 10.4049/jimmunol.1303142.
Publisher:
American Association of Immunologists
Journal:
Journal of Immunology
Publication Date:
Mar-2014
URI:
http://hdl.handle.net/10034/606112
DOI:
10.4049/jimmunol.1303142
Additional Links:
http://www.jimmunol.org/content/early/2014/02/21/jimmunol.1303142.full.pdf+html
Type:
Article
Language:
en_US
ISSN:
0022-1767
EISSN:
1550-6606
Appears in Collections:
Biological Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorO'Connor, Geraldine M.en
dc.contributor.authorVivian, Julian P.en
dc.contributor.authorWidjaja, Jacqueline M.en
dc.contributor.authorBridgeman, John S.en
dc.contributor.authorGostick, Emmaen
dc.contributor.authorLafont, Bernard A.en
dc.contributor.authorAnderson, Stephen K.en
dc.contributor.authorPrice, David A.en
dc.contributor.authorBrooks, Andrew G.en
dc.contributor.authorRossjohn, Jamieen
dc.contributor.authorMcVicar, Daniel W.en
dc.date.accessioned2016-04-20T17:35:04Zen
dc.date.available2016-04-20T17:35:04Zen
dc.date.issued2014-03en
dc.identifier.citationO’Connor, G. M., Vivian, J. P., Widjaja, J. M., Bridgeman, J. S., Gostick, E., Lafont, B. A. P., . . . McVicar, D. W. (2014). Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity. The Journal of Immunology. doi: 10.4049/jimmunol.1303142.en
dc.identifier.issn0022-1767en
dc.identifier.doi10.4049/jimmunol.1303142en
dc.identifier.urihttp://hdl.handle.net/10034/606112en
dc.description.abstractKiller Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation.en
dc.language.isoen_USen
dc.publisherAmerican Association of Immunologistsen
dc.relation.urlhttp://www.jimmunol.org/content/early/2014/02/21/jimmunol.1303142.full.pdf+htmlen
dc.rightsAn error occurred on the license name.*
dc.rightsAn error occurred on the license name.*
dc.rightsAn error occurred on the license name.*
dc.rightsAn error occurred on the license name.*
dc.rightsAn error occurred on the license name.*
dc.rights.uriAn error occurred getting the license - uri.en
dc.subjectNatural Killer Cellsen
dc.subjectKIRen
dc.titleMutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivityen_US
dc.typeArticleen
dc.identifier.eissn1550-6606en
dc.contributor.departmentCancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; Non-Human Primate Immunogenetics and Cellular Immunology Unit, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Basic Science Program, Leidos Biomedical Research Inc., Laboratory of Experimental Immunology, Frederick National Laboratory, Frederick, MD 21702; Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892en
dc.identifier.journalJournal of Immunologyen
dc.date.accepted2014-01-09en
or.grant.openaccessYesen
rioxxterms.funderxxen
rioxxterms.identifier.projectxen
rioxxterms.versionAMen
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