Enhanced effector function of CD8+T cells through thrombin activation of protease-activated receptor 1

Abstract Disruption of vascular integrity by trauma and other tissue insult leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these two processes. The pro-inflammatory function of thrombin is mediated by activation of the Protease-activated receptor-1 (PAR-1). We found that peripheral blood effector memory CD4 and CD8 T lymphocytes expressed PAR-1, and that expression was increased in CD8 T cells from HIV-infected patients. Thrombin enhanced TcR-induced cytokine secretion (IFNγ) in CD8 T cells from healthy controls and HIV infected patients. In addition, thrombin had little chemotactic effect but it was able to inhibited chemotaxis in a CXCL9 gradient. Live microcroscopy revealed that thrombin induced chemokinesis, but not chemotaxis, of CD8 T cells, which led to structural changes, including cell polarization and formation of a structure rich in F-actin and cpERM (phosphorylated ezrin-radexin-moesin) proteins. These findings suggest that thrombin mediates cross-talk between the coagulation system and the adaptive immune system at sites of vascular injury through increased T cell motility and production of pro-inflammatory cytokines and may allow for the accumulation of memory T cells at the site of tissue injury—a physiological mechanism of immune surveillance, inflammation and tissue repair.