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

Lisa L Liu; Johannes Landskron; Eivind H Ask; Monika Enqvist; Ebba Sohlberg; James A Traherne; Quirin Hammer; Jodie P Goodridge; Stella Larsson; Jyothi Jayaraman; Vincent Y S Oei; Marie Schaffer; Kjetil Taskén; Hans-Gustaf Ljunggren; Chiara Romagnani; John Trowsdale; Karl-Johan Malmberg; Vivien Béziat

doi:10.1016/j.celrep.2016.04.005

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

Cell Rep. 2016 May 3;15(5):1088-1099. doi: 10.1016/j.celrep.2016.04.005. Epub 2016 Apr 21.

Authors

Lisa L Liu¹, Johannes Landskron², Eivind H Ask³, Monika Enqvist¹, Ebba Sohlberg¹, James A Traherne⁴, Quirin Hammer⁵, Jodie P Goodridge³, Stella Larsson⁶, Jyothi Jayaraman⁴, Vincent Y S Oei³, Marie Schaffer¹, Kjetil Taskén⁷, Hans-Gustaf Ljunggren¹, Chiara Romagnani⁵, John Trowsdale⁴, Karl-Johan Malmberg⁸, Vivien Béziat⁹

Affiliations

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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity / immunology*
CD2 Antigens / immunology*
CD8-Positive T-Lymphocytes / immunology
Cells, Cultured
Cytomegalovirus / immunology*
Extracellular Signal-Regulated MAP Kinases / metabolism
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Humans
Interferon-gamma / genetics
Interferon-gamma / immunology
Killer Cells, Natural / immunology*
Lymphocyte Activation / immunology
NK Cell Lectin-Like Receptor Subfamily C / deficiency
NK Cell Lectin-Like Receptor Subfamily C / genetics*
Receptors, IgG / genetics
Receptors, IgG / metabolism
Ribosomal Protein S6 / metabolism

Substances

CD2 Antigens
FCGR3B protein, human
GPI-Linked Proteins
KLRC2 protein, human
NK Cell Lectin-Like Receptor Subfamily C
Receptors, IgG
Ribosomal Protein S6
Interferon-gamma
Extracellular Signal-Regulated MAP Kinases