title: Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells.
abstract: Killer immunoglobulin-like receptors (KIRs) interact with human leucocyte antigen (HLA) class I ligands and play a key role in the regulation and activation of NK cells. The functional importance of KIR-HLA interactions has been demonstrated for a number of chronic viral infections, but to date only a few studies have been performed in the context of acute self-limited viral infections. During our investigation of CD8(+) T cell responses to a conserved HLA-B57-restricted epitope derived from dengue virus (DENV) non-structural protein-1 (NS1), we observed substantial binding of the tetrameric complex to non-T/non-B lymphocytes in peripheral blood mononuclear cells (PBMC) from a long-standing clinical cohort in Thailand. We confirmed binding of the NS1 tetramer to CD56(dim) NK cells, which are known to express KIRs. Using depletion studies and KIR-transfected cell lines, we demonstrated further that the NS1 tetramer bound the inhibitory receptor KIR3DL1. Phenotypical analysis of PBMC from HLA-B57(+) subjects with acute DENV infection revealed marked activation of NS1 tetramer-binding natural killer (NK) cells around the time of defervescence in subjects with severe dengue disease. Collectively, our findings indicate that subsets of NK cells are activated relatively late in the course of acute DENV illness and reveal a possible role for specific KIR-HLA interactions in the modulation of disease outcomes.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Townsley
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: O'Connor
authors.affiliation: Ragon Institute at MGH, MIT And Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cosgrove
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Woda
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Co
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Thomas
authors.affiliation: Queen Sirikit National Institute for Child Health, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Kalayanarooj
authors.affiliation: Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: I-K
authors.initials: IK
authors.lastname: Yoon
authors.affiliation: Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: A
authors.initials: A
authors.lastname: Nisalak
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Srikiatkhachorn
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Green
authors.affiliation: Centre for Nephrology and the Anthony Nolan Trust, Royal Free Campus, University College, London, UK.
authors.forename: H A F
authors.initials: HA
authors.lastname: Stephens
authors.affiliation: Cardiff University School of Medicine, Institute of Infection and Immunity, Cardiff, UK.
authors.forename: E
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Cardiff University School of Medicine, Institute of Infection and Immunity, Cardiff, UK.|Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.|Ragon Institute at MGH, MIT And Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Ragon Institute at MGH, MIT And Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Alter
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Rothman
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mathew
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D003716:Dengue Virus / Q000737:chemistry* / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology* / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D054341:Receptors, KIR3DL1 / Q000276:immunology* / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D010446:Peptide Fragments; D054341:Receptors, KIR3DL1; D017361:Viral Nonstructural Proteins
keywords: HLA; KIR; NK; dengue; pathogenesis