Natascha Luther1, Fatemeh Shahneh1, Melanie Brähler1, Franziska Krebs1, Sven Jäckel1, Saravanan Subramaniam1, Christian Stanger1, Tanja Schönfelder1, Bettina Kleis-Fischer1, Christoph Reinhardt1, Hans Christian Probst1, Philip Wenzel1, Katrin Schäfer1, Christian Becker2. 1. From the Department of Dermatology (N.L., F.S., M.B., F.K., C.S., B.K.-F., C.B.), Center for Thrombosis and Hemostasis (CTH) (S.J., S.S., T.S., C.R., P.W., C.B.), Institute for Immunology (H.C.P.), and Center for Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Germany (P.W., K.S.). 2. From the Department of Dermatology (N.L., F.S., M.B., F.K., C.S., B.K.-F., C.B.), Center for Thrombosis and Hemostasis (CTH) (S.J., S.S., T.S., C.R., P.W., C.B.), Institute for Immunology (H.C.P.), and Center for Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Germany (P.W., K.S.). christian.becker@unimedizin-mainz.de.
Abstract
RATIONALE: Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in sterile inflammation in venous thrombosis has not been systematically examined. OBJECTIVE: This study investigated the recruitment, activation, and inflammatory activity of T cells in deep vein thrombosis and its consequences for venous thrombus resolution. METHODS AND RESULTS: CD4+ and CD8+ T cells infiltrate the thrombus and vein wall rapidly on deep vein thrombosis induction and remain in the tissue throughout the thrombus resolution. In the vein wall, recruited T cells largely consist of effector-memory T (TEM) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited TEM receive an immediate antigen-independent activation and produce IFN-γ (interferon) in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of deep vein thrombosis upregulated cytokines and chemokines that synergize to induce antigen-independent IFN-γ production in CD4+ and CD8+ TEM cells. Reducing the number of TEM cells through a depletion recovery procedure, we show that intravenous TEM activation determines neutrophil and monocyte recruitment and delays thrombus neovascularization and resolution. Examining T-cell recruitment in human venous stasis, we show that superficial varicose veins preferentially contain activated memory T cells. CONCLUSIONS: TEM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.
RATIONALE: Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in sterile inflammation in venous thrombosis has not been systematically examined. OBJECTIVE: This study investigated the recruitment, activation, and inflammatory activity of T cells in deep vein thrombosis and its consequences for venous thrombus resolution. METHODS AND RESULTS: CD4+ and CD8+ T cells infiltrate the thrombus and vein wall rapidly on deep vein thrombosis induction and remain in the tissue throughout the thrombus resolution. In the vein wall, recruited T cells largely consist of effector-memory T (TEM) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited TEM receive an immediate antigen-independent activation and produce IFN-γ (interferon) in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of deep vein thrombosis upregulated cytokines and chemokines that synergize to induce antigen-independent IFN-γ production in CD4+ and CD8+ TEM cells. Reducing the number of TEM cells through a depletion recovery procedure, we show that intravenous TEM activation determines neutrophil and monocyte recruitment and delays thrombus neovascularization and resolution. Examining T-cell recruitment in human venous stasis, we show that superficial varicose veins preferentially contain activated memory T cells. CONCLUSIONS: TEM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.
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