Measles Virus Targets DC-SIGN To Enhance Dendritic Cell Infection

ABSTRACT Dendritic cells (DCs) are involved in the pathogenesis of measles virus (MV) infection by inducing immune suppression and possibly spreading the virus from the respiratory tract to lymphatic tissues. It is becoming evident that DC function can be modulated by the involvement of different receptors in pathogen interaction. Therefore, we have investigated the relative contributions of different MV-specific receptors on DCs to MV uptake into and infection of these cells. DCs express the MV receptors CD46 and CD150, and we demonstrate that the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is a novel receptor for laboratory-adapted and wild-type MV strains. The ligands for DC-SIGN are both MV glycoproteins F and H. In contrast to CD46 and CD150, DC-SIGN does not support MV entry, since DC-SIGN does not confer susceptibility when stably expressed in CHO cells. However, DC-SIGN is important for the infection of immature DCs with MV, since both attachment and infection of immature DCs with MV are blocked in the presence of DC-SIGN inhibitors. Our data demonstrate that DC-SIGN is crucial as an attachment receptor to enhance CD46/CD150-mediated infection of DCs in cis. Moreover, MV might not only target DC-SIGN to infect DCs but may also use DC-SIGN for viral transmission and immune suppression.

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Induction of Dendritic Cell Production of Type I and Type III Interferons by Wild-Type and Vaccine Strains of Measles Virus: Role of Defective Interfering RNAs

Journal of Virology ◽

10.1128/jvi.00261-13 ◽

2013 ◽

Vol 87 (14) ◽

pp. 7816-7827 ◽

Cited By ~ 20

Author(s):

R. Shivakoti ◽

M. Siwek ◽

D. Hauer ◽

K. L. W. Schultz ◽

D. E. Griffin

Keyword(s):

Dendritic Cell ◽

Measles Virus ◽

Type I ◽

Wild Type ◽

Cell Production ◽

Type Iii

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Interaction between mannosylated lipoarabinomannan and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin influences dendritic cells maturation and T cell immunity

Cellular Immunology ◽

10.1016/j.cellimm.2011.09.001 ◽

2011 ◽

Vol 272 (1) ◽

pp. 94-101 ◽

Cited By ~ 12

Author(s):

Tingting Wu ◽

Shuliang Guo ◽

Jianjun Wang ◽

Lan Li ◽

Lulu Xu ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

Adhesion Molecule ◽

Intercellular Adhesion ◽

T Cell Immunity ◽

Intercellular Adhesion Molecule ◽

Cell Immunity

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DC-SIGN (dendritic cell-specific ICAM-grabbing non-integrin) and DC-SIGN-related (DC-SIGNR): friend or foe?

Clinical Science ◽

10.1042/cs1040437 ◽

2003 ◽

Vol 104 (4) ◽

pp. 437-446 ◽

Cited By ~ 40

Author(s):

Elizabeth J. SOILLEUX

Keyword(s):

Endothelial Cells ◽

Dendritic Cells ◽

Dendritic Cell ◽

T Lymphocytes ◽

High Efficiency ◽

Immunoglobulin E ◽

Expression Patterns ◽

Intercellular Adhesion Molecule ◽

Carbohydrate Binding ◽

Wide Range

C-type lectins are calcium-dependent carbohydrate-binding proteins with a wide range of biological functions, many of which are related to immunity. DC-SIGN (dendritic cell-specific ICAM-grabbing non-integrin, where ICAM is intercellular adhesion molecule) is a recently described mannose-specific C-type lectin expressed by dendritic cells. Dendritic cells are potent antigen-presenting cells capable of activating T-lymphocytes. DC-SIGN, which is expressed by dendritic cells, binds to ICAM-3 on T-lymphocytes, therefore playing an important role in the activation of T-lymphocytes. DC-SIGN can also bind HIV, and the virus may remain bound to DC-SIGN for protracted periods. DC-SIGN may deliver bound HIV to permissive cell types, mediating infection with high efficiency. A closely related C-type lectin, DC-SIGN-related molecule (DC-SIGNR) has also been described. DC-SIGNR is expressed by restricted subsets of endothelial cells, but has similar ICAM-3 and HIV-binding properties to DC-SIGN. This review describes the mapping of DC-SIGN and DC-SIGNR to chromosome 19p13.3 adjacent to the previously described C-type lectin, CD23 [the low-affinity receptor for immunoglobulin E (FcERII)]. The similar genomic organization of these three genes is discussed and consideration is given to the evolutionary duplications that may underlie this arrangement. Both DC-SIGN and DC-SIGNR possess a neck region, made up of multiple repeats, which supports the ligand-binding domain. Consideration is given to the biological reasons underlying the considerable polymorphism in the numbers of repeats in DC-SIGNR, but not DC-SIGN. The expression patterns of both DC-SIGN and DC-SIGNR are discussed in detail, with particular attention to the expression of both molecules in the placenta, which may have implications for the vertical transmission of HIV. Since dendritic cells may be important in determining the phenotype of many immune responses, via effects on T-lymphocytes, the differential expression of DC-SIGN by particular dendritic cell subsets may have important implications for the immunobiological functions of DC-SIGN. Similarly, the expression of DC-SIGNR by very restricted subsets of endothelial cells may give clues to the function of DC-SIGNR. Finally, the role of DC-SIGN in pathology, particularly in infective and neoplastic processes, is discussed, followed by speculation about likely future developments in this field.

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Cytokine Imbalance after Measles Virus Infection Has No Correlation with Immune Suppression

Journal of Virology ◽

10.1128/jvi.00148-09 ◽

2009 ◽

Vol 83 (14) ◽

pp. 7244-7251 ◽

Cited By ~ 7

Author(s):

Mary Carsillo ◽

Kay Klapproth ◽

Stefan Niewiesk

Keyword(s):

Virus Infection ◽

Immune Suppression ◽

Recombinant Virus ◽

Measles Virus ◽

Vaccine Virus ◽

Gamma Interferon ◽

Wild Type Virus ◽

Wild Type ◽

Spleen Cells ◽

Th2 Response

ABSTRACT Measles virus infection leads to immune suppression. A potential mechanism is the reduction of interleukin 12 (IL-12) secretion during acute measles, resulting in a TH2 response. Studies in humans have reported conflicting results, detecting either a TH2 or a TH1 response. We have investigated the correlation between a TH2 response and immune suppression in specific-pathogen-free inbred cotton rats which were infected with measles vaccine and wild-type viruses. After infection of bone marrow-derived macrophages with wild-type virus, IL-12 secretion was reduced in contrast to the level for vaccine virus infection. In bronchoalveolar lavage cells, IL-12 secretion was suppressed after infection with both wild-type and vaccine virus on days 2, 4, and 6 and was detectable on days 8 and 10. After stimulation of mediastinal lymph node and spleen cells with UV-inactivated measles virus at various time points after infection, gamma interferon but no IL-4 was found. After stimulation with phorbol myristate acetate-ionomycin, high gamma interferon and low IL-4 levels were detected. To investigate whether the secretion of IL-4 contributes to immune suppression, a recombinant vaccine virus was created which secretes cotton rat IL-4. After infection with this recombinant virus, IL-4 secretion was enhanced. However, neither inhibition of concanavalin A-stimulated spleen cells nor keyhole limpet hemocyanin-specific proliferation of spleen cells was altered after infection with the recombinant virus in comparison to the levels with the parental virus. Our data indicate that measles virus infection leads to a decrease in IL-12 secretion and an increase in IL-4 secretion, but this does not seem to correlate with immune suppression.

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Dendritic Cells Recognize Tumor-Specific Glycosylation of Carcinoembryonic Antigen on Colorectal Cancer Cells through Dendritic Cell–Specific Intercellular Adhesion Molecule-3–Grabbing Nonintegrin

Cancer Research ◽

10.1158/0008-5472.can-04-4140 ◽

2005 ◽

Vol 65 (13) ◽

pp. 5935-5944 ◽

Cited By ~ 109

Author(s):

Klaas P.J.M. van Gisbergen ◽

Corlien A. Aarnoudse ◽

Gerrit A. Meijer ◽

Teunis B.H. Geijtenbeek ◽

Yvette van Kooyk

Keyword(s):

Colorectal Cancer ◽

Dendritic Cells ◽

Dendritic Cell ◽

Carcinoembryonic Antigen ◽

Cancer Cells ◽

Adhesion Molecule ◽

Intercellular Adhesion ◽

Intercellular Adhesion Molecule ◽

Colorectal Cancer Cells

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Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress

Journal of Experimental Medicine ◽

10.1084/jem.20160287 ◽

2016 ◽

Vol 213 (12) ◽

pp. 2773-2791 ◽

Cited By ~ 24

Author(s):

Jesus Zamora-Pineda ◽

Ashok Kumar ◽

Jung H. Suh ◽

Meng Zhang ◽

Julie D. Saba

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Stromal Cells ◽

Thymic Epithelial Cells ◽

Homeostatic Regulation ◽

Wild Type ◽

Central Tolerance ◽

Corticomedullary Junction ◽

Sphingosine 1 Phosphate ◽

S1p Lyase

T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)–mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+ dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.

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The Src-Like Adaptor Proteins, SLAP and SLAP2, Regulate Flt3-Dependent Dendritic Cell Development.

Blood ◽

10.1182/blood.v112.11.1535.1535 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1535-1535

Author(s):

Larissa Liontos ◽

C. Jane McGlade

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

B Cell ◽

Progenitor Cells ◽

Adaptor Proteins ◽

Cell Receptor ◽

Sh2 Domain ◽

Wild Type ◽

Knock Out ◽

Knock Out Mice

Abstract The Src-like Adaptor Proteins, SLAP and SLAP2, are hematopoietic adaptor proteins that have been previously shown to act as negative regulators of T- and B-cell signaling. SLAP and SLAP2 work in conjunction with the E3 ubiquitin ligase, c-Cbl, to down regulate the T-cell receptor and other components of the T- and B-cell receptor signaling pathways including ZAP-70 and Syk. SLAP and SLAP2 are expressed in many hematopoietic cell types, including progenitor cells that give rise to cells of both myeloid and lymphoid lineages. Recent evidence indicates a role for SLAP and SLAP2 in regulating hematopoietic receptor tyrosine kinase (RTK) signaling. We have shown that SLAP and SLAP2 interact with CSF-1R/Fms and demonstrated that SLAP2 negatively regulates CSF-1 dependent differentiation of FD-Fms cells. Our recent work demonstrates that both SLAP and SLAP2 interact with the Flt3 receptor in an SH2 domain dependent manner and the interaction was mapped to pY589 and pY591 within the juxtamembrane region of the receptor. To examine the role of SLAP and SLAP2 in Flt3 regulation and signaling in vivo, we utilized Flt3 ligand (Flt3L) to generate dendritic cells from mice lacking both SLAP and SLAP2. Slap1−/− Slap2−/− mice have impaired development of Flt3L-dependent CD11c+ bone marrow-derived dendritic cells (BMDC). In contrast to wild-type mice, Slap1−/− Slap2−/− mice produce 47% ± 9.7% less CD11c+ BMDC after 10 days in culture with Flt3L. Whether the reduction in BMDC numbers is indicative of a defect in the proliferation of Slap1−/−Slap2−/− progenitor cells in response to Flt3L is currently being explored. Although the absolute number of Flt3L-generated BMDC from Slap1−/−Slap2−/− mice is reduced, there are no major differences in the subtype, myeloid (70–90% CD11b+) and lymphoid (4–8% B220+), of DC produced between wild-type and double knock-out mice. To determine whether the reduction in dendritic cell numbers is specific to those generated with Flt3L, we generated BMDC using GM-CSF and IL-4. Both wild-type and double knock-out mice produce similar numbers of CD11c+ BMDC when this combination of cytokines is used. The maturation and activation of Flt3L-generated BMDC from Slap1−/−Slap2−/− mice is being investigated. These data indicate a novel role for SLAP and SLAP2 in the differentiation of Flt3L-dependent dendritic cells.

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Impact of measles virus dendritic-cell infection on Th-cell polarization in vitro

Journal of General Virology ◽

10.1099/vir.0.80125-0 ◽

2004 ◽

Vol 85 (11) ◽

pp. 3239-3247 ◽

Cited By ~ 13

Author(s):

Ingo M. Klagge ◽

Marion Abt ◽

Bianca Fries ◽

Sibylle Schneider-Schaulies

Keyword(s):

Cell Differentiation ◽

Dendritic Cell ◽

Measles Virus ◽

Cell Polarization ◽

Cell Infection ◽

Necrosis Factor Alpha ◽

Th Cell ◽

Cell Commitment ◽

The Impact

Interference of measles virus (MV) with dendritic-cell (DC) functions and deregulation of T-cell differentiation have been proposed to be central to the profound suppression of immune responses to secondary infections up to several weeks after the acute disease. To address the impact of MV infection on the ability of DCs to promote Th-cell differentiation, an in vitro system was used where uninfected, tumour necrosis factor alpha/interleukin (IL) 1β-primed DCs were co-cultured with CD45RO− T cells in the presence of conditioned media from MV-infected DCs primed under neutral or DC-polarizing conditions. It was found that supernatants of DCs infected with an MV vaccine strain strongly promoted Th1 differentation, whereas those obtained from wild-type MV-infected DCs generated a mixed Th1/Th0 response, irrespective of the conditions used for DC priming. Th-cell commitment in this system did not correlate with the production of IL12 p70, IL18 or IL23. Thus, a combination of these or other, as yet undefined, soluble factors is produced upon MV infection of DCs that strongly promotes Th1/Th0 differentiation.

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