5 results on '"Stein, Jens V."'
Search Results
2. HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via ItsNef-Associated Kinase Complex Interface.
- Author
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Lamas-Murua, Miguel, Stolp, Bettina, Kaw, Sheetal, Thoma, Judith, Trautz, Birthe, Ambiel, Ina, Reif, Tatjana, Arora, Sakshi, Imle, Andrea, Tibroni, Nadine, Fackler, Oliver T., Tanaka, Motomu, Tsopoulidis, Nikolaos, Jingxia Wu, Guoliang Cui, Stein, Jens V., and Lyck, Ruth
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DISEASE progression , *HIV , *CD4 antigen , *T cells , *NEGATIVE regulatory factor , *LYMPHOCYTES - Abstract
HIV-1 Nef is a multifunctional protein that optimizes virus spread and promotes immune evasion of infected cells to accelerate disease progression in AIDS patients. As one of its activities, Nef reduces the motility of infected CD4+ T lymphocytes in confined space. In vivo, Nef restricts T lymphocyte homing to lymph nodes as it reduces the ability for extravasation at the diapedesis step. Effects of Nef on T lymphocyte motility are typically mediated by its ability to reduce actin remodeling. However, interference with diapedesis does not depend on residues in Nef required for inhibition of host cell actin dynamics. In search for an alternative mechanism by which Nef could alter T lymphocyte extravasation, we noted that the viral protein interferes with the polarization of primary human CD4+ T lymphocytes upon infection with HIV-1. Expression of Nef alone is sufficient to disrupt T cell polarization, and this effect is conserved among lentiviral Nef proteins. Nef acts by arresting the oscillation of CD4+ T cells between polarized and nonpolarized morphologies. Mapping studies identified the binding site for the Nef-associated kinase complex (NAKC) as critical determinant of this Nef activity and a NAKC-binding-deficient Nef variant fails to impair CD4+ T lymphocyte extravasation and homing to lymph nodes. These results thus imply the disruption of T lymphocyte polarity via its NAKC binding site as a novel mechanism by which lentiviral Nef proteins alter T lymphocyte migration in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
3. HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo.
- Author
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StoIp, Bettina, ImIe, Andrea, Coelho, Fernanda Matos, Hons, Miroslav, Gorina, Roser, Lyck, Ruth, Stein, Jens V., and Fackler, Oliver T.
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HIV , *T cells , *LYMPH nodes , *ACTIN , *LYMPHOCYTES - Abstract
HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef's influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef's ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor. [ABSTRACT FROM AUTHOR]
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- 2012
- Full Text
- View/download PDF
4. In Vivo Analysis of Uropod Function during Physiological T Cell Trafficking.
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Soriano, Silvia F., Hons, Miroslav, Schumann, Kathrin, Kumar, Varsha, Dennier, Timo J., Lyck, Ruth, Sixt, Michael, and Stein, Jens V.
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LYMPHOCYTES , *PHENOTYPES , *CELL culture , *CELL lines , *T cells - Abstract
Migrating lymphocytes acquire a polarized phenotype with a leading and a trailing edge, or uropod. Although in vitro experiments in cell lines or activated primary cell cultures have established that Rho-p 160 coiled-coil kinase (ROCK)-myosin H-mediated uropod contractility is required for integrin de-adhesion on two-dimensional surfaces and nuclear propulsion through narrow pores in three-dimensional matrices, less is known about the role of these two events during the recirculation of primary, nonacti- vated lymphocytes. Using pharmacological antagonists of ROCK and myosin II, we report that inhibition of uropod contractility blocked integrin-independent mouse T cell migration through narrow, but not large, pores in vitro. T cell crawling on chemokine- coated endothelial cells under shear was severely impaired by ROCK inhibition, whereas transendothelial migration was only reduced through endothelial cells with high, but not low, barrier properties. Using three-dimensional thick-tissue imaging and dynamic two-photon microscopy of T cell motility in lymphoid tissue, we demonstrated a significant role for uropod contractility in intraluminal crawling and transendothelial migration through lymph node, but not bone marrow, endothelial cells. Finally, we demonstrated that ICAM-1, but not anatomical constraints or integrin-independent interactions, reduced parenchymal motility of inhibitor-treated I cells within the dense lymphoid microenvironment, thus assigning context-dependent roles for uropod con- traction during lymphocyte recirculation. [ABSTRACT FROM AUTHOR]
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- 2011
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5. Differential Requirements for DOCK2 and Phosphoinositide-3-Kinase γ during T and B Lymphocyte Homing
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Nombela-Arrieta, César, Lacalle, Rosa Ana, Montoya, María C., Kunisaki, Yuya, Megías, Diego, Marqués, Miriam, Carrera, Ana C., Mañes, Santos, Fukui, Yoshinori, Martínez-A, Carlos, and Stein, Jens V.
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LYMPHOCYTES , *CYTOKINES , *INFLAMMATORY mediators , *LYMPHOID tissue - Abstract
Chemokines guide lymphocytes from blood to secondary lymphoid organs by triggering integrin-dependent firm adhesion under vascular flow and directed migration of T and B lymphocytes within lymphoid tissue. Here, we analyze the roles of DOCK2, a mammalian homolog of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, and phosphoinositide-3-kinase (PI3K) during lymphocyte recirculation. DOCK2 mediated efficient lymphocyte migration in a largely PI3K-independent manner, although a minor, PI3K-dependent pathway for migration was observed in wild-type and DOCK2-deficient lymphocytes. In T cells, this residual migration depended mainly on PI3Kγ, whereas other PI3K isoforms were implicated in B cells. In vitro adhesion assays and intravital microscopy of lymphoid organ vasculature uncovered an unexpected defect in integrin activation in DOCK2-/- B cells, whereas lack of DOCK2 did not affect chemokine-triggered integrin activation in T cells. DOCK2 and PI3Kγ thus play distinct roles during T and B cell integrin activation and migration. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
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