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Immunosurveillance of the Liver by Intravascular Effector CD8 + T Cells
Open accessAbstract
Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44. After the initial arrest, CD8 TE actively crawl along liver sinusoids and probe sub-sinusoidal hepatocytes for the presence of antigens by extending cytoplasmic protrusions through endothelial fenestrae. Hepatocellular antigen recognition triggers effector functions in a diapedesis-independent manner and is inhibited by the processes of sinusoidal defenestration and capillarization that characterize liver fibrosis. These findings reveal the dynamic behavior whereby CD8 TE control hepatotropic pathogens and suggest how liver fibrosis might reduce CD8 TE immune surveillance toward infected or transformed hepatocytes.
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“Furthermore, they can extend cellular protrusions through the sinusoidal fenestrae and make contact with the hepatocyte membrane, creating a synapse-like process(101).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [101]
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“They have demonstrated that reducing the access of T cells to the sinusoidal fenestrae inhibits antigen recognition(101).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [101]
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“In a transgenic mouse model of hepatitis B virus infection, in which mouse GP-Ibα is replaced with transgenic human GP-Ibα, it has been observed that effector CD8+ T cells arrest within the sinusoids by docking on platelets, which are already adhered to LSECs. Then, effector CD8+ T cells crawl along the sinusoids and extend their cytoplasmic protrusions through LSEC fenestrae to search for antigen”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [319]
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“It has been shown that platelets are among the first cells to arrive at a site of infection from whence they orchestrate innate and adaptive immune responses,(75,76) by stimulating recruitment of immune cells,(59) including neutrophils,(77,78) macrophages,(61) and CD8(1) T cells.(61,79) Also, platelets can capture inv…”
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Self-citationThe role of liver sinusoidal cells in local hepatic immune surveillance
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The Paradoxical Role of NKG2D in Cancer Immunity
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“CD8+ T cells have the ability to infiltrate the liver and establish contact with hepatocytes in healthy and infected tissues (176, 177) probing for cognate MHC/ peptide on hepatocytes (183).”
BackgroundAdvances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma
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“More recently, in several studies, it was demonstrated that MDSC differentiation from blood monocytes can be promoted by PGE2 secretion in a CD44-dependent manner (76).”
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Effector CD8+ T cell-derived interleukin-10 enhances acute liver immunopathology
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Metadata
- Authors
- Guidotti, L. G., Inverso, D., Sironi, L., Di Lucia, P., Fioravanti, J., Ganzer, L., Fiocchi, A., Vacca, M., Aiolfi, R., Sammicheli, S., Mainetti, M., Cataudella, T., Raimondi, A., Gonzalez-Aseguinolaza, G., Protzer, U., Ruggeri, Z. M., Chisari, F. V., Isogawa, M., Sitia, G., & Iannacone, M.
- Affiliations
- Scripps Research Institute (US)
- Vita-Salute San Raffaele University (IT)
- IRCCS Ospedale San Raffaele (IT)
- Technical University of Munich (DE)
- Corresponding author
- Guidotti, Luca G.
- Iannacone, Matteo
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 161
- Issue
- 3
- Pages
- 486-500
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC11630812
- OpenAlex
- W1971197010
- Cited by
- 323
- References
- 47
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 27 · 2023: 21 · 2022: 29 · 2021: 26 · 2020: 42 · 2019: 26 · 2018: 25 · 2017: 34 · 2016: 30 · 2015: 9
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Giovanni Armenise-Harvard Foundation
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health (HL-42846)
- National Heart, Lung, and Blood Institute (HL 42846, R01HL042846, R37HL042846)
- National Institute of Allergy and Infectious Diseases (AI-40696, R01AI040696)
- FP7 Ideas: European Research Council (281648, 250219)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- CD8+ T cells, hepatitis B virus, CD44, hyaluronic acid, liver sinusoids, endothelial fenestrae, transendothelial migration, liver fibrosis, capillarization
- MeSH terms
- Animals, Cell Movement, Hepatitis B, Hepatitis B virus, Hyaluronic Acid, Liver, Liver Cirrhosis, Mice, Inbred C57BL, Platelet Adhesiveness, Specific Pathogen-Free Organisms, Monitoring, Immunologic, CD8-Positive T-Lymphocytes, Hepatocytes, Endothelial Cells, Mice
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