Inhibitory killer cell immunoglobulin-like receptors strengthen CD8 + T cell–mediated control of HIV-1, HCV, and HTLV-1

Made available in DSpace on 2019-10-06T16:55:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01 Wisconsin Turfgrass Association National Institutes of Health Wellcome Trust Institute for National Strategic Studies Leukemia and Lymphoma Research Seventh Framework Programme Horizon 2020 Medical Research Council Canada National Institute on Drug Abuse National Institute of Child Health and Human Development Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell–mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1–, hepatitis C virus (HCV)–, and human T cell leukemia virus type 1 (HTLV-1)–infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections. Department of Medicine Imperial College London Faculty of Engineering São Paulo State University—UNESP Institute for Infection and Immunity St. George’s University of London International AIDS Vaccine Initiative Human Immunology Laboratory Clinical Research Department London School of Hygiene and Tropical Medicine Divi-sion of Infection and Immunity Cardiff University School of Medicine Nuffield Department of Medicine University of Oxford Oxford NIHR Biomedical Research Centre Immunology Division Department of Pathology University of Cambridge Cancer and Inflammation Program Leidos Biomedical Research Inc. Frederick National Laboratory for Cancer Research Johns Hopkins University Rho San Francisco Department of Public Health Faculty of Medicine University of Southampton Division of Cancer Epidemiology and Genetics National Cancer Institute Ragon Institute of MGH, MIT and Harvard Faculty of Engineering São Paulo State University—UNESP Wisconsin Turfgrass Association: 090323/Z/09/Z National Institutes of Health: 100326Z/12/Z Wellcome Trust: 103865Z/14/Z Institute for National Strategic Studies: 105609/Z/14/Z Leukemia and Lymphoma Research: 15012 Seventh Framework Programme: 317040 Horizon 2020: 695551 Medical Research Council Canada: G1001052 Medical Research Council Canada: J007439 National Institute on Drug Abuse: K24-AI118591 Medical Research Council Canada: MR/L018373/L Medical Research Council Canada: MR/M019829/1 Medical Research Council Canada: MR/P001602/1 National Institutes of Health: R01 DA13324 National Institute on Drug Abuse: R01-DA-12568 National Institute of Child Health and Human Development: R01-HD-41224 National Institute on Drug Abuse: U01-DA-036297