EBI3 regulates the NK cell response to mouse cytomegalovirus infection

Abstract

Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virusinduced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection. The induction of EBI3 protein expression in mouse NK cells is a late activation event. Thus, early activation events of NK cells, such as IFNγ production and CD69 expression, were not affected in EBI3-deficient (Ebi3 −/− ) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral replication in spleen and liver were observed in MCMV-infected Ebi3 −/− and wildtype (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected Ebi3 −/− B6 mice, suggesting that EBI3 plays a role in the establishment of MCMV latency. We detected a decrease in the sustained IL-10 production by NK cells and lower serum levels of IL-10 in the MCMV-infected Ebi3 −/− B6 mice. Furthermore, we observed an increase in dendritic cell maturation markers and an increase in activated CD8 + T cells. Thus, EBI3 dampens the immune response against MCMV infection, resulting in prolonged viral persistence.natural killer cell | EBI3 | cytomegalovirus N atural killer (NK) cells play an essential role in host defense against viral infections, particularly herpesviruses, such as cytomegalovirus (CMV) (1). During infection, NK cell activation is tightly controlled by the integration of signals derived from activating and inhibitory receptors, through the interaction with target or accessory cells, and from cytokine receptors. Several activating NK receptors exist, including the activating killer cell Ig-like receptors (KIRs) in humans, the activating Ly49 receptors in rodents, NKG2D, the natural cytotoxicity receptors (i.e., NKp30, NKp44, and NKp46), and the activating Fc receptor CD16 (2). The activating receptors recognize either stress-induced ligands on viralinfected cells, virus-encoded proteins, or Ig-coated cells. Signals from the activating receptors promote cytoskeletal rearrangements and proliferation, as well as secretion of cytolytic granules and cytokines (2). The inhibitory receptors Ly49 and KIR recognize polymorphic major histocompatibility complex class I ligands that can dampen or prevent the NK cells from attacking self (2).NK cell-mediated control of viral infections has been studied extensively in mice infected with mouse CMV (MCMV). NK cells contribute directly to the early control of MCMV infection by eliminating the virus-infected cells. In C57BL/6 (B6) mice, Ly49H+ NK cells recognize MCMV-infected cells expressing the virus-encoded protein m157. This antigen-specific recognition leads to NK cell activation (3), as well as expansion and differentiation of memory NK cells (4), which is dependent on the DAP12 adapter protein, the costimulatory receptor DNAM-1, and the proinflammatory cytokine IL-12 (4-6). The DAP10 adapter protein and the cytokines IL-33 and IL-18...

KLF12 Regulates Mouse NK Cell Proliferation

“…During MCMV infection, IL-21 induces mouse NK cells to produce IL-10, which affects dendritic cell activation and CD8 + T cell responses (38,(56)(57)(58). We also observed proliferative impairment of KLF12-deficient NK cells during MCMV infection in the mixed BM chimeric mice and in the adoptive transfer of mature NK cells.…”

Accumulation of EBI3 induced by virulentMycobacterium tuberculosisinhibits apoptosis in murine macrophages

“…Using EBI3 −/− mice, several studies have reported that EBI3 regulates NK cell response and is involved in the establishment of mouse cytomegalovirus (MCMV) latency (Jensen et al . 2017 ), suppresses T helper type 1, type 17 and type 2 immune responses against Trypanosoma cruzi parasitemia (Bohme et al . 2016 ), and is associated with M. tb loads in mouse lungs (Zheng et al .…”

Tissue-specific control of latent CMV reactivation by regulatory T cells

“…Interestingly, our previously published data show that Treg from aged mice have significantly increased levels of IL-35p19, suggesting that IL-35 may contribute to suppression of MCMV-specific CD8+ T cell responses [ 76 ]. However, a recent paper showed that IL-35 produced by NK cells during acute MCMV infection promotes, rather than inhibits IL-10 production [ 77 ]. Nonetheless, further studies are required to determine the mechanism by which Treg restrain MCMV-specific CD8+ T cell effector functions and thus promote latent infections.…”