Innate Effector-Memory T Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution
Rationale: Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and non-immune 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 (DVT) and its consequences for venous thrombus resolution.
Methods and Results: CD4+ and CD8+ T cells infiltrate the thrombus and vein wall rapidly upon DVT induction and remain in the tissue throughout thrombus resolution. In the vein wall recruited T cells largely consist of effector-memory T cells (TEM). Using T cell receptor transgenic reporter mice we demonstrate that DVT-recruited TEMreceive an immediate antigen-independent activation and produce IFN-γ in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of DVT up-regulated 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: Effector-memory T cells orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.
- Received June 13, 2016.
- Revision received September 27, 2016.
- Accepted October 5, 2016.