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Critical Role of CD2 Co-stimulation in Adaptive Natural Killer Cell Responses Revealed in NKG2C-Deficient Humans.

Cell Rep. 2016 May 03;15(5):1088-1099. Epub 2016 Apr 21
Lisa L Liu 1 , Johannes Landskron 2 , Eivind H Ask 3 , Monika Enqvist 1 , Ebba Sohlberg 1 , James A Traherne 4 , Quirin Hammer 5 , Jodie P Goodridge 3 , Stella Larsson 6 , Jyothi Jayaraman 4 , Vincent Y S Oei 3 , Marie Schaffer 1 , Kjetil Taskén 7 , Hans-Gustaf Ljunggren 1 , Chiara Romagnani 5 , John Trowsdale 4 , Karl-Johan Malmberg 8 , Vivien Béziat 9
Lisa L Liu 1 , Johannes Landskron 2 , Eivind H Ask 3 , Monika Enqvist 1 , Ebba Sohlberg 1 , James A Traherne 4 , Quirin Hammer 5 , Jodie P Goodridge 3 , Stella Larsson 6 , Jyothi Jayaraman 4 , Vincent Y S Oei 3 , Marie Schaffer 1 , Kjetil Taskén 7 , Hans-Gustaf Ljunggren 1 , Chiara Romagnani 5 , John Trowsdale 4 , Karl-Johan Malmberg 8 , Vivien Béziat 9
+ et al

[No authors listed]

Author information
  • 1 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
  • 2 The Biotechnology Centre of Oslo, University of Oslo, 0349 Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
  • 3 The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway.
  • 4 Cambridge Institute for Medical Research and Department of Pathology, Cambridge University, Cambridge CB2 0XY, UK.
  • 5 Innate Immunity, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, 10117 Berlin, Germany.
  • 6 Clinical Immunology and Transfusion Medicine, Department for Laboratory Medicine, Karolinska Institute, 17177 Stockholm, Sweden.
  • 7 The Biotechnology Centre of Oslo, University of Oslo, 0349 Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, 0318 Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, 0424 Oslo, Norway.
  • 8 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway. Electronic address: k.j.malmberg@medisin.uio.no.
  • 9 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; University Paris Descartes, Imagine Institute, 75270 Paris, France. Electronic address: vivien.beziat@inserm.fr.

摘要

Infection by human cytomegalovirus (HCMV) leads to NKG2C-driven expansion of adaptive natural killer (NK) cells, contributing to host defense. However, approximately 4% of all humans carry a homozygous deletion of the gene that encodes NKG2C (NKG2C(-/-)). Assessment of NK cell repertoires in 60 NKG2C(-/-) donors revealed a broad range of NK cell populations displaying characteristic footprints of adaptive NK cells, including a terminally differentiated phenotype, functional reprogramming, and epigenetic remodeling of the interferon (IFN)-γ promoter. We found that both NKG2C(-) and NKG2C(+) adaptive NK cells expressed high levels of CD2, which synergistically enhanced ERK and S6RP phosphorylation following CD16 ligation. Notably, CD2 co-stimulation was critical for the ability of adaptive NK cells to respond to antibody-coated target cells. These results reveal an unexpected redundancy in the human NK cell response to HCMV and suggest that CD2 provides "signal 2" in antibody-driven adaptive NK cell responses.

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