CMV Infection of Human Sinusoidal Endothelium Regulates Hepatic T Cell Recruitment and Activation

BACKGROUND & AIMS: Human cytomegalovirus infection (HCMV) is associated with an increased morbidity after liver transplantation by facilitating allograft rejection and accelerating underlying hepatic inflammation. We hypothesized that human hepatic sinusoidal endothelial cells infected with HCMV possess the capacity to modulate allogeneic T cell recruitment and activation thereby providing a plausible mechanism of how HCMV infection is able to enhance hepatic immune activation.

METHODS: Human hepatic sinusoidal endothelial cells were isolated from explanted livers and infected with recombinant endotheliotropic HCMV. We used static and flow-based models to quantify adhesion and transendothelial migration of allogeneic T cell subsets and determine their post-migratory phenotype and function.

RESULTS: HCMV infection of primary human hepatic sinusoidal endothelial cells facilitated ICAM-1 and CXCL10-dependent CD4 T cell transendothelial migration under physiological levels of shear stress. Recruited T cells were primarily non-virus-specific CXCR3(hi) effector memory T cells, which demonstrated features of LFA3-dependent Th1 activation after migration. In parallel, regulatory T cells were more strongly recruited via infected hepatic endothelium and retained a suppressive phenotype following transmigration.

CONCLUSIONS: The ability of infected hepatic endothelium to recruit distinct functional CD4 T cell subsets shows how HCMV facilitates hepatic inflammation and immune activation and may simultaneously favor virus persistence.