A Distinct Subpopulation of Human NK Cells Restricts B Cell Transformation by EBV

Abstract

Natural Killer (NK) cells constitute the first line of defense against pathogens and transformed cells. NK cells mature in secondary lymphoid organs including tonsils, where common pathogens like the Epstein-Barr virus (EBV) enter the host and potentially imprint differentiating cells, which then patrol the body via the blood stream. We therefore set out to characterize a distinct human NK cell population in tonsils, which produces high amounts of the immunomodulatory and anti-viral cytokine IFN-γ. We found that (i) the tonsilar IFN-γhigh NK cell subset is CD56brightNKG2A+CD94+CD54+CD62L−; (ii) is present in tonsils ex vivo and is more mature than other CD56bright NK cells in tonsils and less mature than other NK cells in blood; (iii) shows very low plasticity even after prolonged cytokine stimulation; (iv) accumulates in tonsils of EBV-carriers and (v) is able to potently restrict EBV-induced transformation of B cells. Thus, we characterized a distinct and stable IFN-γhigh NK cell subpopulation that can specifically restrict malignant transformation of EBV-infected B cells. This subset should be exploited for future development of cell-based therapeutic approaches in EBV-associated malignancies.

Role for early-differentiated natural killer cells in infectious mononucleosis

“…49 Indeed, this could result from ongoing lytic EBV replication at these sites in asymptomatic EBV carriers. 46 Additionally, we determined that the increased CD56 dim NKG2A…”

The interplay between Epstein–Barr virus and B lymphocytes: implications for infection, immunity, and disease

“…Studies in immunodeficient mice reconstituted with human cells indicate that NK cells are particularly important in controlling lytic EBV infection (12). Munz and colleagues suggest that a IFN-γ high , CD56 bright NKG2A + CD94 + CD54 + CD62L − subset of NK cells found in tonsils of EBV carriers are critical in restricting transformation of B cells (13). NK cells also appear to have a role in controlling chronic viral infection.…”

Innate Immune Recognition of EBV

“…Besides the described restriction of EBVinduced transformation in vitro (Lünemann et al 2013), several case reports of patients with selective immunodeficiencies, including NK cells deficiencies and EBV-associated tumors, have documented the potential role of NK cells exerting antineoplastic effects (recently reviewed in Orange 2013; Rickinson et al 2014). Clear causal relationships, however, remain elusive.…”

“…In tonsils, which are the likely portal of entry for EBV, the most mature NK cells are the CD56 bright cells (Freud et al 2014). A distinct subset of these can restrict EBV-induced transformation in autologous B cells in vitro very efficiently, probably via IFN gamma (Lünemann et al 2013;Strowig et al 2008). This subset also has the potency to restrict EBV infection of autologous B cells, and this seems to happen within the first 4 days (Lünemann and Nadal, unpublished observations).…”

“…In addition, DCs will hereby further activate and recruit other immune cells such as granulocytes and NK cells (Fig. 2), which have been shown to inhibit B-cell transformation and target lytic replicating cells very efficiently (Lünemann et al 2013;Pappworth et al 2007;Chijioke et al 2013). An overview of current knowledge and hypotheses on cellular interactions during EBV infection is summarized in Fig.…”