Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

Abstract

Liver sinusoidal endothelial cell lectin (LSECtin) was recently reported to suppress intrahepatic T cell immunity and to limit immune-mediated liver injury. However, its role in the outcome and pathogenesis of viral infection has not yet been elucidated. Using a mouse model infected with a hepatotropic adenovirus, we found that the absence of LSECtin led to a higher frequency of intrahepatic effector CTLs. These cells produced higher levels of antiviral cytokines and cytotoxic factors and exhibited an increased expression of the transcription factors T-bet and Runx3. This phenotype observed in the LSECtin-knockout cells mediated a more efficient virus-specific cytotoxity compared with that of wild-type cells. As a consequence, LSECtin deficiency significantly accelerated liver adenovirus clearance. In contrast, LSECtin upregulation in the liver delayed viral clearance; this delayed clearance was accompanied by the downregulation of the antiviral activity of CTLs. We further constructed an immunocompetent mouse model of acute hepatitis B viral infection to demonstrate that LSECtin significantly delayed the clearance of hepatitis B virus from blood and infected hepatocytes by limiting the frequency of hepatitis B virus–specific IFN-γ–producing cells. Consistent with this function, LSECtin was upregulated in the liver of mouse models of viral hepatitis. Taken together, our results suggest that LSECtin may facilitate the reduction of liver inflammation at the cost of delaying virus clearance and that this effect might be hijacked by the virus as an escape mechanism.

Liver sinusoidal endothelial cells: Physiology and role in liver diseases

“…as observed for hepatitis B and hepatitis C viruses [137,138]. Lectin expressed by LSECs is not only involved in regulation of the entry of viruses but also in the regulation of their clearance by modulating functions of T cells as it has been shown for adenovirus [139]. LSECs can also be infected with CMV (cytomegalovirus) which upregulates ICAM-1 and CXCL10 expression, thus favoring CD4 T cell transendothelial migration.…”

Tumor immune response and immunotherapy in gastric cancer

“…CTLA-4 is continuously expressed in Tregs and supports the immunosuppressive function of Tregs [19]. LAG-3 expression is increased in activated T cells and natural killer cells, and its ligands are MHC class II, LSECtin, and galectin-3 [20,21]. LAG-3 inhibits T cell proliferation and cytokine production.…”

Myeloid C-Type Lectin Receptors in Viral Recognition and Antiviral Immunity

“…Using LSECtin-deficient mice in adenovirus infection and HBV replication as murine models for viral hepatitis, Liu et al . demonstrated that LSECtin facilitated the reduction of liver inflammation by delaying virus clearance and that this process could be hijacked by viruses as an immune evasion mechanism [81]. …”