Enhanced Effector Function of CD8+ T Cells From Healthy Controls and HIV-Infected Patients Occurs Through Thrombin Activation of Protease-Activated Receptor 1

Abstract

Disruption of vascular integrity by trauma and other tissue insults leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these 2 processes. The proinflammatory function of thrombin is mediated by activation of 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 human immunodeficiency virus (HIV)-infected patients. Thrombin enhanced cytokine secretion in CD8(+) T cells from healthy controls and HIV-infected patients. In addition, 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 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 proinflammatory cytokines.

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

“…Less is known about the effects of PAR-1 activation on adaptive immune cells. We found that treatment with thrombin induces dose-dependent PAR-1 internalization in CD8 + T cells and confirmed an earlier report that thrombin augments IFN-γ production in purified CD8 + T cells in vitro [20]. This effect was also seen with the PAR-1 agonist TFLLR and could be blocked in both cases with the PAR-1 antagonist vorapaxar.…”

“…Consistent with the findings of Catalfamo et al [20], there was a small but significant increase in the percentage of CCR7 neg CD8 + T cells that exhibited IFN-γ production in the presence of thrombin ( Figure 5A), and the enhancement could be blocked with vorapaxar. Surprisingly, when we repeated the stimulation experiments with unseparated PBMC preparations, we observed an neg CD8 + T cells expressing IFN-γ in PBMC cultures after stimulation with anti-CD3/anti-CD28 for 6 hours in the absence (0 U/mL) or presence (0.5 U/mL) of thrombin (n = 9; right).…”

“…Circulating immune cells can interact with soluble coagulation elements through expression of the thrombin receptor PAR-1. A recent report found increased surface PAR-1 expression on CD8 + T cells in viremic HIV-infected patients but not patients receiving ART [20]. Here we show that even among aviremic HIV-infected persons, PAR-1 surface expression is increased on all CD8 + T cells and is particularly elevated on CD8 + T cells expressing CX3CR1.…”

“…In addition to promoting clot formation, thrombin can also cleave an extracellular portion of protease-activated receptor 1 (PAR-1), subsequently activating the receptor through the newly generated N-terminus [19]. PAR-1 is expressed on the surface of CD8 + T cells as well as on monocytes, platelets, and endothelial cells [20][21][22]. A recent report indicated that PAR-1 expression is increased on the surface of CD8 + T cells from treated HIVinfected patients and that PAR-1 activation directly increases CD8 + T-cell effector function [20].…”

“…PAR-1 is expressed on the surface of CD8 + T cells as well as on monocytes, platelets, and endothelial cells [20][21][22]. A recent report indicated that PAR-1 expression is increased on the surface of CD8 + T cells from treated HIVinfected patients and that PAR-1 activation directly increases CD8 + T-cell effector function [20].…”