Natural Killer Cell Responses during Human γ-Herpesvirus Infections.

Christian Münz

doi:10.3390/vaccines9060655

Abstract

Herpesviruses are main sculptors of natural killer (NK) cell repertoires. While the β-herpesvirus human cytomegalovirus (CMV) drives the accumulation of adaptive NKG2C-positive NK cells, the human γ-herpesvirus Epstein–Barr virus (EBV) expands early differentiated NKG2A-positive NK cells. While adaptive NK cells support adaptive immunity by antibody-dependent cellular cytotoxicity, NKG2A-positive NK cells seem to preferentially target lytic EBV replicating B cells. The importance of this restriction of EBV replication during γ-herpesvirus pathogenesis will be discussed. Furthermore, the modification of EBV-driven NK cell expansion by coinfections, including by the other human γ-herpesvirus Kaposi sarcoma-associated herpesvirus (KSHV), will be summarized.

Highlights

Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, 8057 Zürich, Switzerland; Abstract: Herpesviruses are main sculptors of natural killer (NK) cell repertoires
CD56dim CD16+ NKG2A− killer immunoglobulin-like receptors (KIRs)+ NK cells seem to give rise to either CD56dim CD16+ NKG2C+ KIR+ adaptive NK cells that accumulate during CMV infection or to CD56− CD16+ NKG2A− KIR+ terminally differentiated NK cells that are enriched in Kaposi sarcoma-associated herpesvirus (KSHV)-coinfected individuals
Since coinfection with the malaria parasite Plasmodium falciparum (Pf) is associated with an increased risk of developing Burkitt’s lymphoma [86] and since certain KIR receptor-HLA ligand pairs are associated with the immune control of this parasite [87,88], coinfection with Pf might be in part responsible for the observed accumulation of CD56− CD16+ NK cells

Summary

Human γ-Herpesvirus Infections and Associated Pathologies

The two human γ-herpesviruses Epstein–Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with lymphomas and carcinomas [1,2]. B cell infection by EBV in submucosal secondary lymphoid tissues like the tonsils leads to the expression of six nuclear antigens (EBNA1, 2, 3A, 3B, 3C, -LP) and two latent membrane proteins (LMP1 and 2), as well as two Epstein–Barr virus-encoded small RNAs (EBERs) and more than 40 miRNAs in naïve B cells [10,11]. This so-called latency III program is thought to drive B cell differentiation into the germinal center reaction. In this review I will discuss the evidence that natural killer (NK) cells are part of this immune control and might be harnessed against EBV- and KSHV-associated pathologies

Genetic Evidence for Immune Control of Human γ-Herpesviruses by NK Cells

NK Cell Phenotype and Function during EBV Infection

Modulation of NK Cell Responses by KSHV

Harnessing NK Cells against γ-Herpesvirus-Associated Pathologies

Findings

Conclusions and Outlook