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Review
. 2023 Mar 22;15(6):1914.
doi: 10.3390/cancers15061914.

The Role of NK Cells in EBV Infection and Related Diseases: Current Understanding and Hints for Novel Therapies

Maria G Desimio  1 , Daniela A Covino  1 , Beatrice Rivalta  1   2 , Caterina Cancrini  1   2 , Margherita Doria  1
Affiliations
Review

The Role of NK Cells in EBV Infection and Related Diseases: Current Understanding and Hints for Novel Therapies

Maria G Desimio et al. Cancers (Basel). .

Abstract

The Epstein-Barr virus (EBV) is a ubiquitous herpesvirus most often transmitted during infancy and infecting the vast majority of human beings. Usually, EBV infection is nearly asymptomatic and results in life-long persistency of the virus in a latent state under the control of the host immune system. Yet EBV can cause an acute infectious mononucleosis (IM), particularly in adolescents, and is associated with several malignancies and severe diseases that pose a serious threat to individuals with specific inborn error of immunity (IEI). While there is a general consensus on the requirement for functional CD8 T cells to control EBV infection, the role of the natural killer (NK) cells of the innate arm of immunity is more enigmatic. Here we provide an overview of the interaction between EBV and NK cells in the immunocompetent host as well as in the context of primary and secondary immunodeficiencies. Moreover, we report in vitro data on the mechanisms that regulate the capacity of NK cells to recognize and kill EBV-infected cell targets and discuss the potential of recently optimized NK cell-based immunotherapies for the treatment of EBV-associated diseases.

Keywords: EBV; EBV+ lymphoproliferative disease; EBV+ malignancy; Epstein–Barr virus; IEI; IM; NK cell; immunodeficiency; immunotherapy; inborn error of immunity; infectious mononucleosis; natural killer cell.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of NK cell functions in various phases of EBV infection. In secondary lymphoid tissues such as tonsils, NK cells exert a first-line defense against EBV that crosses the mucosal epithelium during primary infection (left panel); the antiviral functions of NK cells include direct killing of EBV-infected B cells, production of a wide range of cytokines (e.g., IFN-γ, TNF, and granulocyte/monocyte colony-stimulating factor, GM-CSF) that facilitate activation of T cells and innate immune cells such as dendritic cells (DCs), and secretion of chemokines that attract effector lymphocytes and myeloid cells at the sites of infection. During the acute phase of infection, a large expansion of activated CD8 T cells, many of which are EBV-specific, occurs coincidentally with the development of symptoms (expansion phase, central panel); in this phase, NK cells are also expanded, specifically an NKG2A+KIR− NK cell population armed with the capacity to recognize and kill EBV-infected cells ex vivo and to eliminate highly activated CD8 T cells in vivo in a mouse model. In the infected host, EBV persists in latently infected B cells that are killed inefficiently by NK cells, possibly because they express high levels of HLA-I molecules recognized by inhibitory receptors (iKIR) and few/no NK cell-activating ligands; upon EBV reactivation and productive lytic replication, infected cells become highly susceptible to NK cell-mediated killing because of HLA-I downregulation and induction of ligands for activating receptors such as NKG2D.
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