Cell Reports
Volume 15, Issue 5, 3 May 2016, Pages 1088-1099
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Article
Critical Role of CD2 Co-stimulation in Adaptive Natural Killer Cell Responses Revealed in NKG2C-Deficient Humans

https://doi.org/10.1016/j.celrep.2016.04.005Get rights and content
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Highlights

  • NKG2C−/− donors have normal T cell immunity to cytomegalovirus

  • NKG2C−/− donors have normal frequencies of adaptive NK cells

  • CD2 is critical for antibody-triggered responses by adaptive NK cells

  • CD2 synergizes with NKG2C in classical adaptive NK cells

Summary

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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