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Japanese encephalitis virus (JEV) is a frequent cause of acute and epidemic viral encephalitis. However, there is little information describing the mechanisms by which JEV subverts immune responses that may predispose the host to secondary infections. In this study, we found that JEV induced the subversion of CD8+ T cell responses in a transient manner that was closely correlated with viral multiplication. Subsequently, analysis using a TCR-transgenic system revealed that CD8+ T cells purified from JEV-infected mice showed impaired responses, and that naive CD8+ T cells adoptively transferred into JEV-infected recipients showed less expanded responses. Furthermore, JEV altered the splenic dendritic cell (DC) subpopulation via preferential depletion of CD8α+CD11c+ DCs without changing the plasmacytoid DCs and induced a significant reduction in the surface expression of MHC class II and CD40, but not MHC class I, CD80, and CD86 molecules. Finally, JEV was shown to inhibit the presentation of MHC class I-restricted Ag in DCs, and this immune suppression was ameliorated via the activation of DCs by TLR agonists. Collectively, our data indicate that JEV precludes the functions of Ag-presenting machinery, such as depletion of CD8α+CD11c+ DCs and downregulation of MHC class I-restricted Ag presentation, thereby leading to immune subversion of CD8+ T cells.

Dendritic cells (DCs) are potent initiators of T cell-mediated immunity that undergo maturation during viral infections. However, few reports describing the interactions of DCs with Japanese encephalitis virus (JEV), which remains the most frequent cause of acute and epidemic viral encephalitis, are available. In this study, we investigated the interaction of JEV with DCs and macrophages. JEV replicated its viral RNA in both cells with different efficiency, and JEV infection of macrophages followed the classical activation pathway of up-regulation of tested costimulatory molecules and proinflammatory cytokine production (IL-6, TNF-α, and IL-12). On the contrary, JEV-infected DCs failed to up-regulate costimulatory molecules such as CD40 and MHC class II. Of more interest, along with production of proinflammatory cytokines, DCs infected by JEV released antiinflammatory cytokine IL-10, which was not detected in macrophages. Moreover, signaling through MyD88 molecule, a pan-adaptor molecule of TLRs, and p38 MAPK in JEV-infected DCs was found to play a role in the production of cytokines and subversion of primary CD4+ and CD8+ T cell responses. We also found that IL-10 released from JEV-infected DCs led to a reduction in the priming of CD8+ T cells, but not CD4+ T cells. Taken together, our data suggest that JEV induces functional impairment of DCs through MyD88-dependent and -independent pathways, which subsequently leads to poor CD4+ and CD8+ T cell responses, resulting in boosting viral survival and dissemination in the body.

Dendritic cells (DCs) as professional antigen-presenting cells have been known to play critical role in the initiation and modulation of the adaptive immune responses. Here, we will discuss the roles of CD11c+ DCs and functional modulation of inflammatory monocytes CD11b+Ly-6C+ in the progression of acute viral encephalitis caused by infection with Japanese encephalitis virus (JEV). The ablation of DCs exacerbated acute viral encephalitis and neuroinflammatory reactions following JEV infection. Also, the ablation of CD11c+ DCs induced early infiltration of inflammatory monocytes CD11b+Ly-6C+ in the central nervous system (CNS) and provided activated microglia and macrophages. This severed neuroinflammatory reaction was accompanied with early production of huge amount of pro-inflammatory cytokines, but type I IFN expression was not blunted in CD11c+ DC-depleted mice. In particular, the ablation of CD11c+ DCs induced immatured phenotype and morphology of CD11b+Ly-6C+ monocytes in lymphoid and inflammatory tissues. CD11b+Ly-6C+ monocyte developed in DC-depleted mice showed reduced antigen-presenting capacity and recovered phenotype when CD11c+ DCs were increased. These results suggest that CD11c+ DCs could regulate the differentiation of inflammatory monocytes CD11b+Ly-6C+ to affect clinical severity of JE.

Dendritic cells (DCs) are potent initiator of T cell-mediated immunity and undergo maturation during viral infections. However, few reports describing the interactions of DCs with Japanese encephalitis virus (JEV), which remains the most cause of acute and epidemic viral encephalitis, are available. In this study, we investigated the interaction of JEV with DCs and macrophages. JEV replicated its viral RNA in both cells with different efficiency, and we found that JEV infection of macrophages followed classical activation pathway of upregulation of costimulatory molecules and proinflammatory cytokine production (IL-6, TNF-¥á, and IL-12). On the contrary, JEV-infected DCs failed to upregulate costimulatory molecules (CD40, CD80, CD86, and MHC class II). Of more interest, along with production of proinflammatory cytokines, DCs infected by JEV released anti-inflammatory cytokine IL-10, which was not detected in macrophages. Moreover, signaling through MyD88 molecule, a pan-adaptor molecule of Toll-like receptors (TLRs), and p38 MAPK in JEV-infected DCs was found to have roles in production of cytokines and subversion of primary CD4+ and CD8+ T cell responses. We also found that IL-10 released from JEV-infected DCs mediated the reduced priming of CD8+ T cells but not CD4+ T cells. Our data suggest that JEV induce functional impairment of DCs through MyD88-dependent and independent pathways, which subsequently lead to poor CD4+ and CD8+ T cell responses, resulting in boosting viral survival and dissemination in the body.