Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution

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 (T_EM) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited T_EM 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⁺ T_EM cells. Reducing the number of T_EM cells through a depletion recovery procedure, we show that intravenous T_EM 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: T_EM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.

Keywords: chemokines; cytokines; immune system; lymphocytes; venous thrombosis.