Determinants of hepatic effector CD8+ T cell dynamics

Abstract

Antigen-specific effector CD8⁺ T cells play a critical role in controlling hepatic infections, such as the one caused by hepatitis B virus (HBV). We review here recent results where we coupled advanced dynamic imaging with dedicated mouse models of HBV pathogenesis to show that circulating effector CD8⁺ T cells aimed at viral clearance initially arrest in liver sinusoids by preferentially docking onto platelets that have previously adhered to liver sinusoids. Upon detachment from platelets, effector CD8⁺ T cells crawl within the sinusoids irrespective of bloodstream direction, and probe underlying hepatocytes for the presence of antigen by extending filopodia-like protrusions through the sinusoidal fenestrae. Effector CD8⁺ T cells recognize hepatocellular antigen and perform effector functions (i.e., IFN-γ production and hepatocyte killing) while still in the intravascular space. They later extravasate in the parenchyma. Finally, we provide our perspective on how, in the next few years, intravital microscopy might shed new light on yet unresolved issues with particular regard to identifying the determinants of hepatic effector CD8⁺ T cell trafficking, antigen recognition and effector functions during hepatocellular carcinoma and understanding the mechanisms whereby intrahepatic T cell priming induces functionally defective T cell responses. A better understanding of how adaptive immunity mediates pathogen clearance and tumor elimination may lead to improved vaccination and treatment strategies for immunotherapy of infectious diseases and cancer.

Keywords: CD8(+) T cells; Hepatitis B virus; Intravital imaging; Leukocyte trafficking; Mouse models; Platelets.