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    Oral Communication

    Immunothrombosis

    Mechanisms of Thromboinflammation

    OC 47.3 - Negative feedback control of coagulation by T helper cells in immunothrombosis

    Monday, June 26, 2023
    15:15 – 15:30 ET
    Room: 524
    Session Available As: On-Demand

      Presenting Author(s)

    • Tonina T. Mueller, MD (she/her/hers)

      Medizinische Klinik und Poliklinik I, Ludwig-Maximilian University Munich
      Munich, Bayern, Germany

      • Co-Author(s)

    • MW

      Mona Wohlrab

      PhD candidate
      Institut für Laboratoriumsmedizin Klinikum der Universität München Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • TL

      Torben LangHeinrich

      PhD candidate
      Institut für Laboratoriumsmedizin Klinikum der Universität München Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • MT

      Manovriti Thakur

      PhD
      Institut für Laboratoriumsmedizin Klinikum der Universität München Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • RB

      Rebecca Block

      MD candidate
      Institut für Laboratoriumsmedizin Klinikum der Universität München Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • CT

      Claudia Tersteeg

      Prof., Dr.
      Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
      Kortrijk, West-Vlaanderen, Belgium

    • MW

      Małgorzata Wygrecka

      Principal Investigator, Assistant Professor, Department of Medical Biochemistry
      Center for Infection and Genomics of the Lung, Faculty of Medicine, Justus Liebig University, Giessen, Germany
      Giessen, Hessen, Germany

    • HI

      Hellen Ishikawa-Ankerhold

      PhD
      Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • CS

      Christian Schulz

      professor
      Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • SH

      Samuel Huber

      professor
      I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
      Hamburg, Hamburg, Germany

    • Steffen Massberg, MD

      professor
      Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    • BE

      Bernd Engelmann

      professor
      Institut für Laboratoriumsmedizin Klinikum der Universität München Ludwig-Maximilians- University Munich, Germany
      Munich, Bayern, Germany

    Background: Coagulation is activated in the microcirculation during systemic infections. Immune mechanisms protecting against dysregulation of coagulation are incompletely described.

    Aims: Aim of this study was to explore the role of CD4+ T cells in immunothrombosis.

    Methods: Mice (C57Bl6/J or photoconvertible KAEDE mice) were infected with E.coli or S.pneumoniae. Intravascular fibrin formation, thrombus development, immune cell recruitment and immune cell-specific proteins were detected by immunohistochemistry. KAEDE mice were used to test intestinal origin of liver Th17 cells. Immune cell movements in the liver microcirculation were analyzed by intravital microscopy. f12-/- (factor XII) and plg-/-(plasminogen) mice were used to test contributions of contact pathway and fibrinolysis. CD4+ T cells were depleted using aCD4-antibody. LFA-1 and uPA were blocked by antibody injections. CD4+ T cells were isolated from uninfected and infected mice and healthy human donors for in vitro fibrinolysis assays and RNAseq. Autopsy samples from SARS-CoV-2 and influenza patients were analyzed by immunohistochemistry.

    Results: T helper cells, mainly consisting of Th17 cells that partially originated from the small intestine, were recruited rapidly to infected liver microvessels. Intravital imaging showed fibrin-dependent arrest and LFA-1-mediated migration of CD4+ T cells. In f12-/- and rivaroxaban-treated mice with reduced fibrin levels T cell arrest was decreased. T cell immobilization was enhanced in plg-/- mice. Depletion of CD4+ T cells strongly amplified intravascular coagulation and non-occlusive thrombosis in the liver and the lung during bacterial infections. CD4+ T cells expressed and bound all major fibrinolysis activators. Mouse and human CD4+ T cell-dependent fibrinolysis was enhanced by LFA-1-mediated T cell activation in vivo and in vitro. In human lung autopsy samples we detected strictly inverse relations between arrest of CD4+ T cells and micro- and macrovascular thrombosis in SARS-CoV-2 and influenza virus infections.

    Conclusion(s): T helper cell recruitment and intravascular coagulation are connected by regulatory loops that negatively regulate immunothrombosis.

    Learning Objectives:

    • describe immune cell dynamics in immunothrombosis after systemic bacterial infection
    • define the role of CD4+ T cells in coagulation regulation
    • describe mechanism of T helper cell mediated fibrinolysis in systemic bacterial infection.