Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD‐L1 on dendritic cells

Abstract

The mechanisms underlying Japanese encephalitis virus (JEV) pathogenesis need to be thoroughly explored to delineate therapeutic approaches. It is believed that JEV manipulates the innate and adaptive compartments of the host's immune system to evade immune response and cross the blood-brain barrier. The present study was thus designed to investigate the functional modulation of DCs after exposure to JEV and to assess the consequences on CD4 Eur. J. Immunol. 2014Immunol. . 44: 1363Immunol. -1374 Introduction Japanese encephalitis virus (JEV) is the cause of the most dreaded mosquito-borne disease and epidemic viral encephalitis in the world [1][2][3]. The expanding geographical range and JEV's ability to cause devastating epidemics in nonimmune populations demand an urgent effort toward the development of efficient antiviral therapies [4] or of alternate strategies that can reduce JEV immunopathogenesis. A significant number of studies illustrate the importance of crossing the blood-brain barrier (BBB) for pathogenesis and clinical manifestations of JEV infection [5]. JEV induces the activation of endothelial cells to increase the adhesion and transport the infected leukocytes across the BBB [6]. These findings imply that JEV requires escaping immune surveillance at the periphery, until the essential alterations occur at the BBB. Therefore, modulation of immune cells at the periphery is a prerequisite. In particular, upon modulation of the cells at periphery, JEV generates a favorable microenvironment that facilitates the alteration of BBB integrity [7][8][9][10].The paramount protective function of humoral immunity is well documented in human cases of JEV [11][12][13] as well as in animal models [14][15][16][17] Results Replication-competent JEV induces the phenotypic maturation of immature DCsDCs are known to initiate immune responses to invading pathogens. We hypothesized that DCs are privileged targets for modulation by JEV to subvert the immune system and establish successful infection. To evaluate this hypothesis, we first analyzed the effect of JEV on DC activation. The results demonstrate that JEV induces the maturation of DCs at 1 MOI (Fig. 1). The expression of activation markers such as HLA-DR and CD40, and of co-stimulatory molecules such as CD80/B7.1, CD86/B7.2, and CD83, was significantly upregulated on JEV-infected DCs as compared with mock-infected or replication-incompetent JEV-treated DCs ( Fig. 1A-E). We further analyzed the expression of DC-SIGN, which plays a crucial role in DC responses to pathogens [26]. The expression of DC-SIGN was not affected by JEV infection (Fig. 1F), in contrast to observations made with dengue virus, where DC-SIGN expression has been documented to be related to the levels of viral infection [27]. However, a role for DC-SIGN as a possible pattern recognition receptor for JEV cannot be excluded and further investigations are required to explore the role of DC-SIGN in JEV pathogenesis. Interestingly, PD-L1 expression was significantly increased upon infection by re...

Pigs expressing the human inhibitory ligand PD‐L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties

“…The most striking effect of PD‐1‐triggered signaling on cellular level is decreased proliferation of CD4 + T cells. In addition, PD‐1 signals have been described to promote CD4 + CD25 + Foxp3 + regulatory T cells . This is in line with the observation that PD‐1/PD‐L1‐mediated regulation of immune responses to allografts in vivo depends on the presence of CD4 + CD25 + Foxp3 + cells .…”

Interactions of human microglia cells with Japanese encephalitis virus

“…Our results revealed a tendency of expression of MHC class II on activated CX 3 CR1 + -human microglia upon exposure to JEV. MHC class II is also increased on JEV-exposed human MoDC, but not MDM [11, 12]. MHC class II is involved in the reactivation of virus-specific CD4 + T-lymphocytes.…”

“…In fact, human blood monocytes survive from productive infection by JEV and can maintain infectious virus for 5 days [10]. Human blood monocyte-derived dendritic cells (MoDC) and monocyte-derived macrophages (MDM) support virus replication in vitro [11, 12]. …”

T-regulatory cells as part of strategy of immune evasion by pathogens

“…Several mechanisms of suppres sive activity have been described upon direct cell-cell contacts between Tregs and their target cells. In particu lar, Tregs were shown to produce cytokines IL 10, TGF β, and IL 35 that inhibit vital processes in effector T lymphocytes and other immune cells [21,22].…”

“…PD 1 receptors and their ligands are negative regulators of immune response that belong to the immunoglobulin superfamily and structurally homologous to B7 costimulatory mole cules. JEV escapes from the host's immune system by modulating crosstalk between PD L1 on dendritic cells and PD 1 on T cells during antigen presentation, thus blocking a TCR (T cell receptor) dependent signaling pathway [21].…”