Epstein-Barr Virus-Specific Immune Control by Innate Lymphocytes

Abstract

Epstein-Barr virus (EBV) is a potent B cell transforming pathogen in humans. In most persistently EBV-infected individuals, potent cytotoxic lymphocyte responses prevent EBV-associated pathologies. In addition to comprehensive adaptive T cell responses, several innate lymphocyte populations seem to target different stages of EBV infection and are compromised in primary immunodeficiencies that render individuals susceptible to symptomatic EBV infection. In this mini-review, I will highlight the functions of natural killer, γδ T cells, and natural killer T cells during innate immune responses to EBV. These innate lymphocyte populations seem to restrict both lytic replication and transforming latent EBV antigen expression. The mechanisms underlying the recognition of these different EBV infection programs by the respective innate lymphocytes are just starting to become unraveled, but will provide immunotherapeutic strategies to target pathologies that are associated with the different EBV infection programs.

Keywords: CD27/CD70; NKG2D; Vγ9Vδ2 T cells; infectious mononucleosis; lytic replication; natural killer T cells; natural killer cells.

Figure 1

Innate lymphocytes target different stages of Epstein–Barr virus (EBV) infection. EBV was suggested to drive B cell differentiation by expressing all eight latent EBV proteins (latency III) in tonsillar naïve B cells and rescuing germinal center (GC) B cells with the expression of three latent EBV proteins (latency II) toward memory B cells. In homeostatically proliferating memory B cells, only one latent EBV protein is expressed for viral genome maintenance (latency I). From this infected memory B cell pool, EBV can reactivate into virus producing lytic replication, most likely after B cell receptor engagement. Natural killer (NK) cells have been shown to preferentially recognize lytic EBV replication and NKG2D has been suggested as an activating receptor involved in this recognition after upregulation of its MICA/B and ULBP ligands. In a subgroup of infected individuals, Vγ9Vδ2 T cells can be stimulated by EBV latency I Burkitt’s lymphoma cell lines and recognize these by mevalonate metabolite recognition in a butyrophilin (BTN) 3A1-dependent fashion. Finally, natural killer T (NKT) cells have been suggested to recognize EBV latency II in Hodgkin’s lymphoma cell lines, presumably by recognizing glycolipid presentation on CD1d. Thus, cytotoxic innate lymphocytes can target different stages of EBV infection.