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

Abstract

SummaryInfection 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.

Cognate HLA absence in trans diminishes human NK cell education

“…Additionally, the loss of NK cell-mediated protection correlated with an elevated CD8 + T cell expansion in NK cell-depleted mixed reconstituted huNSG mice ( Figure 7D). Finally, in order to investigate the formation of an adaptive NK cell compartment upon EBV infection, we assessed surface markers that had been implicated in NK cell memory formation during viral infections (42)(43)(44). In accordance with published data, adaptive NK cells were phenotypically characterized by a lack of Syk expression (Supplemental Figure 7, A and B) as well as lower levels of FcεRIγ and NKp46 (Supplemental Figure 7, C and D).…”

“…It has been suggested that this expansion might result from the engagement of the CD94/NKG2C receptor by HLA-E on HCMV-infected cells in combination with IL-15 and/ or IL-12 produced by infected or bystander myeloid cells (48,49). Indeed, these cytokines might be crucial for the accumulation of terminally differentiated NK cells in HCMV carriers, because NKG2C-deficient individuals also accumulate NK cell populations, which are reminiscent in their phenotype and function of NKG2C + NK cells in the absence of this receptor (44). In contrast, EBV drives the expansion of preferentially KIR -, early differentiated NK cell populations, possibly through the direct recognition of lytically EBV replicating B cells (25,26) that do not efficiently produce the NK cell-differentiating cytokines IL-15 and IL-12.…”

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

“…NKG2C + CD57 + adaptive NK cells typically express self-specific KIR and are therefore both educated and terminally differentiated (35). Adaptive NK cells are an attractive NK-cell subset for cancer immunotherapy due to robust cytotoxicity, cytokine release and potential for long-term persistence (42). We found that CAR-engineered adaptive NK cells responded better than all other subsets, demonstrating that differentiation-driven functional potential serves as a good basis for CAR signaling.…”

Memory responses of natural killer cells

“…‘Signal 1’ via CD94/NKG2C receptor engagement of HLA-E was shown to drive expansion of NK cells in vitro , and blocking this interaction using antibodies against CD94 or NKG2C, or knocking down HLA-E with a short hairpin RNA, greatly impaired NK cell expansion [66]. Recent studies have suggested that a co-stimulatory ‘Signal 2’ may be provided through the interaction of CD2, which is highly expressed by adaptive NK cells [67], and its cognate ligand CD58, which is upregulated by HCMV-infected fibroblasts [68]. This interaction enhanced production of IFN-γ and TNF-α in response to HCMV-infected fibroblasts [68] or CD16-crosslinking [67]; however, its role in promoting expansion or generation of memory-like properties in vivo has not been determined.…”