NK Cell Influence on the Outcome of Primary Epstein-Barr Virus Infection

Abstract

The herpesvirus Epstein-Barr virus (EBV) was discovered as the first human candidate tumor virus in Burkitt's lymphoma more than 50 years ago. Despite its strong growth transforming capacity, more than 90% of the human adult population carries this virus asymptomatically under near perfect immune control. The mode of primary EBV infection is in part responsible for EBV-associated diseases, including Hodgkin's lymphoma. It is, therefore, important to understand which circumstances lead to symptomatic primary EBV infection, called infectious mononucleosis (IM). Innate immune control of lytic viral replication by early-differentiated natural killer (NK) cells was found to attenuate IM symptoms and continuous loss of the respective NK cell subset during the first decade of life might predispose for IM during adolescence. In this review, we discuss the evidence that NK cells are involved in the immune control of EBV, mechanisms by which they might detect and control lytic EBV replication, and compare NK cell subpopulations that expand during different human herpesvirus infections.

Keywords: DNAM-1; NKG2D; humanized mice; infectious mononucleosis; lytic EBV infection.

Figure 1

Role of NK cells in the immune control of the EBV life cycle. Epstein–Barr virus (EBV) is transmitted via saliva exchange and infects submucosal B cells. In infected naïve B cells, the latency III EBV program can be found (EBNA1, 2, 3A–C, LP, and LMP1 and 2). Activation via EBV infection drives infected B cells into differentiation. In resulting germinal center B cells, latency II EBV infection can be found (EBNA1, LMP1 and 2). These EBV proteins allow EBV-infected B cells to survive and enter the memory B cell pool. In memory B cells, all EBV proteins expression is switched off (latency 0). Upon B cell receptor cross-linking, the lytic EBV cycle is activated due to plasma cell differentiation, which allows epithelial cell infection for further amplification of infectious virus before shedding into saliva. NK cells target lytically EBV replicating cells via their activating NKG2D and DNAM-1 receptors. It remains unclear if also lytically EBV replicating epithelial cells can be recognized by NK cells.

Figure 2

EBV and HCMV expand different NK cell populations. Epstein–Barr virus (EBV) expands early-differentiated NKG2A/CD94, NTB-A, 2B4, CD27, CD16, NKG2D, and DNAM-1-positive NK cells, which after expansion upregulate the senescence marker CD57. Human cytomegalovirus (HCMV) in contrast expands late-differentiated CD94/NKG2C, CD16, CD2, KIR, and CD57-positive NK cells.