J Immunol. 2026 Feb 9;215(2):vkaf366. doi: 10.1093/jimmun/vkaf366.
ABSTRACT
Epstein-Barr virus (EBV) is a human γ-herpesvirus that establishes latency and lifelong infection in B cells. Failure to control latent EBV infection can result in a variety of malignancies, including lymphoproliferative diseases. Studies have implicated natural killer (NK) cells as critical in the host defense against lytic and latent EBV infection. To fully characterize NK cells that respond to latently infected cells, we generated a panel of EBV+ B lymphoblastoid cell lines (EBV+ LCL) and performed coculture experiments with autologous primary NK cells. EBV-responsive NK cells were analyzed for functional and phenotypic markers using mass cytometry. In addition to expression of the inhibitory NK cell receptor NKG2A, EBV-responsive NK cells express high levels of the NKp30 and NKG2D activating receptors which were shown to be important in mediating cytotoxicity of EBV+ LCL. NK cells from cohorts of EBV seropositive and EBV seronegative children were examined by mass cytometry for NK cell receptor expression and identified 4 NKG2A+ clusters, including the NKG2A+2B4+CD56+CD16-CD57-NKG2C-NKp30+NKG2D+ population. The importance of the NKG2A: HLA-E immune checkpoint axis was established using both HLA-E knockout EBV+ LCL and antibody blockade of NKG2A which demonstrated enhanced NK-mediated cytotoxicity in the absence of NKG2A-HLA-E interactions. Taken together, our results support that NKG2A+ NK cells are educated and functionally cytotoxic against EBV-infected B cells and suggest therapeutics targeting the NKG2A: HLA-E immune checkpoint axis would be a good option for EBV-associated malignancies.
PMID:41795284 | DOI:10.1093/jimmun/vkaf366