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

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.

Graphical Abstract

Highlights

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

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

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

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  CD2 synergizes with NKG2C in classical adaptive NK cells

Abstract

Liu et al. demonstrate the emergence of redundant adaptive NK cell subsets in NKG2C ^−/− donors. Functional studies unraveled a critical role for CD2 in antibody-dependent responses by adaptive NK cells, paving the way for new strategies to harness their cytotoxic potential in cell therapy.