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

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

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.

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.

PMID:
27117418
PMCID:
PMC4858565
DOI:
10.1016/j.celrep.2016.04.005
[Indexed for MEDLINE]
Free PMC Article

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