Critical Role of CD2 Co-stimulation in Adaptive Natural Killer Cell Responses Revealed in NKG2C-Deficient Humans.
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.
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
Lisa L
LL
Liu
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.
Johannes
J
Landskron
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.
Eivind H
EH
Ask
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
Monika
M
Enqvist
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
Ebba
E
Sohlberg
Cambridge Institute for Medical Research and Department of Pathology, Cambridge University, Cambridge CB2 0XY, UK.
James A
JA
Traherne
Innate Immunity, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, 10117 Berlin, Germany.
Quirin
Q
Hammer
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.
Jodie P
JP
Goodridge
Clinical Immunology and Transfusion Medicine, Department for Laboratory Medicine, Karolinska Institute, 17177 Stockholm, Sweden.
Stella
S
Larsson
Cambridge Institute for Medical Research and Department of Pathology, Cambridge University, Cambridge CB2 0XY, UK.
Jyothi
J
Jayaraman
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.
Vincent Y S
VYS
Oei
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
Marie
M
Schaffer
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.
Kjetil
K
Taskén
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
Hans-Gustaf
HG
Ljunggren
Innate Immunity, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, 10117 Berlin, Germany.
Chiara
C
Romagnani
Cambridge Institute for Medical Research and Department of Pathology, Cambridge University, Cambridge CB2 0XY, UK.
John
J
Trowsdale
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.
Karl-Johan
KJ
Malmberg
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.
Vivien
V
Béziat
D056704:Adaptive Immunity / Q000276:immunology*; D018801:CD2 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000172:deficiency / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism
D018801:CD2 Antigens; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C527059:KLRC2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D017452:Receptors, IgG; D038601:Ribosomal Protein S6; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases