DC-SIGN and CD150 Have Distinct Roles in Transmission of Measles Virus from Dendritic Cells to T-Lymphocytes

Measles virus (MV) is among the most infectious viruses that affect humans and is transmitted via the respiratory route. In macaques, MV primarily infects lymphocytes and dendritic cells (DCs). Little is known about the initial target cell for MV infection. Since DCs bridge the peripheral mucosal tissues with lymphoid tissues, we hypothesize that DCs are the initial target cells that capture MV in the respiratory tract and transport the virus to the lymphoid tissues where MV is transmitted to lymphocytes. Recently, we have demonstrated that the C-type lectin DC-SIGN interacts with MV and enhances infection of DCs in cis. Using immunofluorescence microscopy, we demonstrate that DC-SIGN+ DCs are abundantly present just below the epithelia of the respiratory tract. DC-SIGN+ DCs efficiently present MV-derived antigens to CD4+ T-lymphocytes after antigen uptake via either CD150 or DC-SIGN in vitro. However, DC-SIGN+ DCs also mediate transmission of MV to CD4+ and CD8+ T-lymphocytes. We distinguished two different transmission routes that were either dependent or independent on direct DC infection. DC-SIGN and CD150 are both involved in direct DC infection and subsequent transmission of de novo synthesized virus. However, DC-SIGN, but not CD150, mediates trans-infection of MV to T-lymphocytes independent of DC infection. Together these data suggest a prominent role for DCs during the initiation, dissemination, and clearance of MV infection

Signal Inhibitory Receptor on Leukocytes-1 is highly expressed on lung monocytes, but absent on mononuclear phagocytes in skin and colon

Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is expressed on human blood monocytes and granulocytes and inhibits myeloid effector functions. On monocytes, but not granulocytes, SIRL-1 expression is low or absent in individuals with the single nucleotide polymorphism (SNP) rs612529C. The expression of SIRL-1 in tissue and the influence of rs612529 hereon is currently unknown. Here, we used flow cytometry to determine SIRL-1 expression on immune cells in human blood and three barrier tissues; skin, colon and lung. SIRL-1 was expressed by virtually all neutrophils and eosinophils in these tissues. In contrast, SIRL-1 was not expressed by monocytederived cells in skin and colon, whereas it was highly expressed by lung classical monocytes. Lung monocytes from individuals with a rs612529C allele had decreased SIRL-1 expression, consistent with the genotype association in blood. Within the different monocyte subsets in blood and lung, SIRL-1 expression was highest in classical monocytes and lowest in nonclassical monocytes. SIRL-1 was not expressed by dendritic cells in blood and barrier tissues. Together, these results indicate that SIRL-1 is differentially expressed on phagocyte subsets in blood and barrier tissues, and that its expression on monocytes is genotype- and tissue-specific. Immune regulation of monocytes by SIRL-1 may be of particular importance in the lun

C-type lectins on dendritic cells. Bittersweet interactions with viruses

Dendritische cellen (DC’s) zijn als verkenners van het immuunsysteem constant op zoek naar ziekteverwekkers. Wanneer DC’s een ziekteverwekker tegenkomen, activeren ze het immuunsysteem om de indringer te vernietigen. Michiel Van der Vlist beschrijft hoe hiv-1 (de meest voorkomende variant van het aidsvirus) en het mazelenvirus DC’s kunnen misbruiken om infectie met het virus te bevorderen. Hij bracht in beeld hoe hiv-1 gebruikmaakt van afweersignalen om de eigen vermenigvuldiging te stimuleren. Ook laat hij zien dat het mazelenvirus kan meeliften met de DC’s om op die manier meer cellen te kunnen infecteren

The Effect of Natural Space on Nearby Property Prices:Accounting for Perceived Attractiveness

This paper estimates the effect of attractive natural space on Dutch residential property prices. We operationalize attractive natural spaces by combining land use data with unique data on the perceived attractiveness of natural spaces. In our main results, the effect of attractive natural space on property prices falls from 16.0% for properties within 0.5 km, to 1.6% for properties up to 7 km away. Our findings advance existing hedonic studies by verifying that economic benefits of living near natural space extend over a larger distance. This has important implications for public policy regarding investment in natural space near residential areas.</p

The Effect of Natural Space on Nearby Property Prices: Accounting for Perceived Attractiveness

This paper estimates the effect of attractive natural space on Dutch residential property prices. We operationalize attractive natural spaces by combining land use data with unique data on the perceived attractiveness of natural spaces. In our main results, the effect of attractive natural space on property prices falls from 16.0% for properties within 0.5 km, to 1.6% for properties up to 7 km away. Our findings advance existing hedonic studies by verifying that economic benefits of living near natural space extend over a larger distance. This has important implications for public policy regarding investment in natural space near residential areas

Immune checkpoints and rheumatic diseases : what can cancer immunotherapy teach us?

The recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the inhibitory receptors cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in the regulation of antitumour immune responses. However, blocking signalling by these inhibitory immune checkpoint receptors is also associated with substantial inflammatory effects that can resemble autoimmune responses, which is consistent with the role of these receptors in protecting the host from excessive inflammation. The human genome encodes over 300 inhibitory receptors, which represent as many opportunities to modulate inflammation in a disease-specific and tissue-specific manner. We argue that rheumatologists and oncologists should join forces to study these inhibitory immune molecules. An improved understanding of these immune checkpoints will enable both fields to make progress in exploiting inhibitory immune receptors therapeutically. In this Review, we discuss data from studies reporting the adverse inflammatory effects of cancer therapies that target immune checkpoints. We discuss the potential implications of these findings on the biological understanding of autoimmune rheumatic diseases and highlight therapeutic strategies that could be used to target inhibitory receptors for the treatment of these conditions

Innate signaling in HIV-1 infection of dendritic cells

This review summarizes the current knowledge of innate signaling events that are involved in HIV-1 infection. We here focus on dendritic cells, which are among the first cells that encounter HIV-1 after exposure. HIV-1 triggers multiple pattern recognition receptors on dendritic cells that facilitate infection and transmission to T cells. Triggering of the C-type lectin DC-SIGN induces signals that promote HIV-1 replication in dendritic cells and transmission to T cells. Similarly, dendritic cell immunoreceptor has been shown to bind HIV-1 and facilitate transmission to T cells. The cytosolic sensors TRIM5 and cyclophilin A recognize capsid proteins and activate antiviral responses to prevent HIV-1 infection. Moreover, activation of mammalian target of rapamycin (mTOR) by HIV downregulates autophagy preventing adaptive immune responses. Dendritic cells express an array of pattern recognition receptors that are involved in HIV-1 infection. However, HIV-1 dampens signaling by these receptors leading to suppressed responses or takes advantage of their signaling for its own benefi

Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori

Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1-CNK-Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our study reveals another level of plasticity in tailoring adaptive immunity to pathogen