Abstract
Epstein–Barr virus (EBV) is a human γ-herpesvirus that establishes latency and lifelong infection in host B cells while achieving a balance with the host immune response. When the immune system is perturbed through immunosuppression or immunodeficiency, however, these latently infected B cells can give rise to aggressive B cell lymphomas. Natural killer (NK) cells are regarded as critical in the early immune response to viral infection, but their role in controlling expansion of infected B cells is not understood. Here, we report that NK cells from healthy human donors display increased killing of autologous B lymphoblastoid cell lines (LCLs) harboring latent EBV compared to primary B cells. Coculture of NK cells with autologous EBV+ LCL identifies an NK cell population that produces IFNγ and mobilizes the cytotoxic granule protein CD107a. Multi-parameter flow cytometry and Boolean analysis reveal that these functional cells are enriched for expression of the NK cell receptor NKG2A. Further, NKG2A+ NK cells more efficiently lyse autologous LCL than do NKG2A− NK cells. More specifically, NKG2A+2B4+CD16−CD57−NKG2C−NKG2D+ cells constitute the predominant NK cell population that responds to latently infected autologous EBV+ B cells. Thus, a subset of NK cells is enhanced for the ability to recognize and eliminate autologous, EBV-infected transformed cells, laying the groundwork for harnessing this subset for therapeutic use in EBV+ malignancies.
Highlights
Epstein–Barr virus (EBV) is a ubiquitous γ-herpesvirus that persists as a chronic, asymptomatic infection in over 90% of the adult human population [1]
We compared Natural killer (NK) cell ligand staining on EBV+ lymphoblastoid cell lines (LCLs) with primary autologous CD19+ B cells (Figure 1; Figure S1A in Supplementary Material)
To further characterize the NK cell subsets responding to latent EBV+ LCL, we examined the NK cell response to EBV using combinations of the six NK receptor (NKR) 2B4, CD16, CD57, NKG2A, NKG2C, and NKG2D
Summary
Epstein–Barr virus (EBV) is a ubiquitous γ-herpesvirus that persists as a chronic, asymptomatic infection in over 90% of the adult human population [1]. EBV preferentially establishes infection in naïve tonsillar B cells. EBV remains in the lytic phase of infection in a minority of cells, producing infectious viral particles that are spread by oral transmission. Latent infection is established in the vast majority of infected cells and is responsible for driving infected B cells into the memory B cell reservoir, where the virus persists for the lifetime of the host; in healthy carriers, an average of 10 of every million peripheral blood memory B cells are EBV-infected [1, 2]. Distinct viral proteins from both lytic and latent cycles of infection elicit a robust cellular immune response in the host.
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