Abstract
Cells of the innate immune system act in synergy to provide a first line of defense against pathogens. Here we describe that dendritic cells (DCs), matured with viral products or mimics thereof, including Epstein-Barr virus (EBV), activated natural killer (NK) cells more efficiently than other mature DC preparations. CD56brightCD16− NK cells, which are enriched in human secondary lymphoid tissues, responded primarily to this DC activation. DCs elicited 50-fold stronger interferon-γ (IFN-γ) secretion from tonsilar NK cells than from peripheral blood NK cells, reaching levels that inhibited B cell transformation by EBV. In fact, 100- to 1,000-fold less tonsilar than peripheral blood NK cells were required to achieve the same protection in vitro, indicating that innate immune control of EBV by NK cells is most efficient at this primary site of EBV infection. The high IFN-γ concentrations, produced by tonsilar NK cells, delayed latent EBV antigen expression, resulting in decreased B cell proliferation during the first week after EBV infection in vitro. These results suggest that NK cell activation by DCs can limit primary EBV infection in tonsils until adaptive immunity establishes immune control of this persistent and oncogenic human pathogen.
Highlights
natural killer (NK) cells of tonsils, the primary site of Epstein-Barr virus (EBV) infection, inhibit B cell transformation by EBV after they have been activated by dendritic cells (DCs)
NK cells primarily prevent B cell transformation by EBV via secretion of the anti-viral cytokine IFN-c, and NK cells from tonsils and lymph nodes produce 5-fold more of this cytokine than their peripheral blood counterparts. These data suggest that specialized NK cells in tonsils, the mucosal entry site of EBV, can be efficiently stimulated by EBVactivated DCs, and limit EBV-induced B cell transformation until EBV-specific immune control by other components of the immune system is established
Because the tonsils are the primary site of EBV infection, we investigated whether the DC/NK cell crosstalk could trigger NK cells to limit B cell transformation during EBV infection
Summary
Epstein-Barr (EBV) is a lymphotropic c-herpes virus infecting over 90% of the human adult population [1,2]. A striking feature that the virus shares with other c-herpes viruses is its oncogenic potential This transforming property can be observed in vitro and in vivo both in immunocompetent and more frequently in immunosuppressed individuals. In the latter group, EBV causes tumors such as posttransplant lymphoproliferative disease and immunoblastic lymphoma, whereas, nasopharyngeal carcinoma, Hodgkin’s disease and endemic Burkitt’s lymphoma are the most prominent EBV-associated malignancies in immunocompetent individuals [3]. In male patients with Xlinked lymphoproliferative disease (XLP), who frequently succumb after primary EBV infection to EBV-induced lymphomas, a mutation in the SAP gene leads to defective recognition of EBV-transformed B cells by NK cells [5,6,7]. NK cells may be involved in the early phase of the EBV-specific immune response
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