Editors' ChoiceImmunology

Out of reach

See allHide authors and affiliations

Science Translational Medicine  06 May 2015:
Vol. 7, Issue 286, pp. 286ec73
DOI: 10.1126/scitranslmed.aab3973

Hepatitis B virus (HBV) lurks in the liver, causing a chronic liver infection that, although asymptomic in many individuals, can eventually lead to cirrhosis and liver cancer. Immune cells attempt to seek out these hidden viruses through a process called immune surveillance; however, exactly how immune cells probe the liver has remained unclear. Effector CD8+ T lymphocytes (CD8 TE) have been believed to recognize pathogen-infected liver parenchymal cells and then kill the infected cells after extravasation from the post-capillary venules through the process of leukocyte diapedesis. However, liver sinusoids are relatively porous, and sinusoidal leukocyte adhesion often occurs independent of rolling. This led the authors to hypothesize that CD8 TE migration and function in the liver may differ from the classic paradigm. In their elegant study, Guidotti et al. show that hepatic CD8 TE homing is independent of adhesion molecules, chemokines, or antigen recognition, and instead depends on platelet “docking,” which allows CD8 TEs to perform immune surveillance and effector functions while still in the intravascular space.

When HBV-specific CD8 TE cells were transferred into HBV replication-competent mice, they adhered to hepatic sinusoids (rather than post-capillary venules), regardless of the location of HBV-antigen–producing hepatocytes. Platelet depletion, but not inhibition of adhesion molecules, chemokines, or the degree of liver inflammation, reduced CD8 TE accumulation. CD8 TEs docked preferentially to sites of transient platelet micro-aggregates on liver sinusoidal epithelial cells (LSEC), and this required platelet-expressed CD44 interacting with sinusoidal hyaluronan. Once “docked,” CD8 TEs crawled along liver sinusoids, and after recognizing hepatocellular antigens, expressed IFN-γ. Indeed, apoptotic hepatocytes were preferentially detected juxtaposed to these cells. Using a combination of three-dimensional (3D) confocal fluorescence and transmission electron microscopy, the authors demonstrated that CD8 TEs extended small protrusions through LSEC fenestrations to probe underlying hepatocytes. Chronic treatment with arsenite, which reduces LSEC fenestrations, or CCl4, which leads to deposition of extracellular matrix in the space of Disse, reduced in vivo CD8 TE antigen recognition and liver damage, but not hepatic platelet-dependent homing.

Although the authors did not demonstrate a direct link between impaired intravascular CD8 TE immune surveillance and hepatic carcinogenesis, their findings offer a model by which liver fibrosis creates a physical barrier to T cell immune surveillance and an environment that favors the development of hepatocellular carcinoma.

L. G. Guidotti et al., Immunosurveillance of the liver by intravascular effector CD8+ T cells. Cell 161, 486–500 (2015). [Abstract]

Navigate This Article