Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1.
Killer cell immunoglobulin-like receptors (KIRs) play an important role in the activation of natural killer (NK) cells, which in turn contribute to the effective immune control of many viral infections. In the context of HIV infection, the closely related KIR3DL1 and KIR3DS1 molecules, in particular, have been associated with disease outcome. Inhibitory signals via KIR3DL1 are disrupted by downregulation of HLA class I ligands on the infected cell surface and can also be impacted by changes in the presented peptide repertoire. In contrast, the activatory ligands for KIR3DS1 remain obscure. We used a structure-driven approach to define the characteristics of HLA class I-restricted peptides that interact with KIR3DL1 and KIR3DS1. In the case of HLA-B*57:01, we used this knowledge to identify bona fide HIV-derived peptide epitopes with similar properties. Two such peptides facilitated productive interactions between HLA-B*57:01 and KIR3DS1. These data reveal the presence of KIR3DS1 ligands within the HIV-specific peptide repertoire presented by a protective HLA class I allotype, thereby enhancing our mechanistic understanding of the processes that enable NK cells to impact disease outcome.


OBJECTIVE
Natural killer (NK) cells are implicated as determinants of immune control in many viral infections, but the precise molecular mechanisms that initiate and control these responses are unclear. The activating receptor KIR3DS1 in combination with HLA-Bw4 has been associated with better outcomes in HIV infection. However, evidence of a direct interaction between these molecules is lacking. In this study, we demonstrate that KIR3DS1 recognition of HLA-Bw4 is peptide dependent. We also identify HIV-derived peptide epitopes presented by the protective HLA-B*57:01 allotype that facilitate productive interactions with KIR3DS1. Collectively, these findings suggest a mechanism whereby changes in the peptide repertoire associated with viral infection provide a trigger for KIR3DS1 engagement and NK cell activation.
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Geraldine M
GM
O'Connor
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
Julian P
JP
Vivian
Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, Wales, United Kingdom.
Emma
E
Gostick
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
Phillip
P
Pymm
Non-Human Primate Immunogenetics and Cellular Immunology Unit, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Bernard A P
BA
Lafont
Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, Wales, United Kingdom Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
David A
DA
Price
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, Wales, United Kingdom.
Jamie
J
Rossjohn
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
Andrew G
AG
Brooks
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA mcvicard@mail.nih.gov.
Daniel W
DW
McVicar
D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006678:HIV / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology; D054730:Protein Interaction Domains and Motifs; D054341:Receptors, KIR3DL1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054349:Receptors, KIR3DS1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; D054298:Human Immunodeficiency Virus Proteins; C515083:KIR3DL1 protein, human; D009842:Oligopeptides; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1