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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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InfluentialSelf-citationIntravascular Immune Surveillance by CXCR6+ NKT Cells Patrolling Liver Sinusoids
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Items 201–293 of 293
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“In HBV infection, the liver is also considered the site of naïve HBV-specific T-cell priming due to the particular structure of the liver: the speed of blood flow in the sinusoid is much slower than that in the periphery (17–19), which allows circulating T cells to recognize MHC-peptide complexes presented by hepatiti…”
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“In addition, a unique anatomical feature of the liver, where CD8 T cells share localization with Kupffer cells in the sinusoid, enables circulating anti - PD - 1 antibody to easily access PD - 1+ CD8 T cells in this organ (51, 52).”
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“These findings suggest that an inflammatory response initiated by respiratory tract infection subsequently promoted the expansion of CD8+ T cells in the liver [6].”
Immune Response to Occult Hepatitis B Virus Infection Among Hemodialysis Patients: a review
Mussa, A., Ismail, N. H., Syed, N. H., Talib, M., Siddig, A., Hassan, R., Mohamud, R., & Hashim, N. H. H. N. (2024) · The Microbe · doi:10.1016/j.microb.2024.100176 · Cited by 1
Ursu, C.-P., Ciocan, A., Ursu, Ș., Ciocan, R. A., Gherman, C. D., Cordoș, A., Vălean, D., Pop, R. S., Furcea, L., Procopeț, B., et al. (2024) · Cancers · doi:10.3390/cancers16071427 · Cited by 3
“Therefore, a therapeutic approach that reduces CD8+ T cell liver damage and prevents or delays fibrosis could be efficient in hepatocellular carcinoma [22,23].”
BackgroundInflammatory microenvironment and immunotherapy in hepatocellular carcinoma
Liu, L., & Liu, B. (2023) · European Journal of Inflammation · doi:10.1177/1721727x231172025 · Cited by 1
“44 Combination with ICIs improves the immunocidal activity of ACTs, but ultimately these immunoreactive cells must also in fi ltrate into the cancerous tissue, and researchers have been investigating factors that in fl uence in fi ltration of secondary metastatic cells, such as liver fi - brosis…”
BackgroundFumagalli, V., Ravà, M., Marotta, D., Lucia, P. D., Laura, C., Sala, E., Grillo, M., Bono, E., Giustini, L., Perucchini, C., et al. (2021) · bioRxiv · doi:10.1101/2021.08.06.455382 · Cited by 1
Self-citationShiha, G., Toson, E., & EL-Sawah, R. (2020) · Scientific Journal for Damietta Faculty of Science · doi:10.21608/sjdfs.2020.195001 · Cited by 1
Early treatment of chronic hepatitis B in children: Everything to play for?
Bertoletti, A., Gill, U., & Kennedy, P. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.12.007 · Cited by 1
Mechanisms behind TB, HBV, and HIV chronic infections
Durantel, D., Kusters, I. C., Louis, J. A., Manel, N., Ottenhoff, T. H. M., Picot, V., & Saadatian‐Elahi, M. (2017) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2017.09.008 · Cited by 1
“The adaptive response is also thought to be deficient during chronic HBV infection (Tang et al., 2016; Guidotti et al., 2015).”
BackgroundSacci, J., Hollingdale, M., & Sedegah, M. (2017) · Pathogens and Disease · doi:10.1093/femspd/ftx051 · Cited by 1
Immunopathogenesis of Hepatitis B Virus Infection
Chua, C., Salimzadeh, L., & Gehring, A. J. (2021) · Springer eBooks · doi:10.1007/978-981-16-3615-8_4
In Vitro and Ex Vivo Models to Study T Cell Migration Through the Human Liver Parenchyma
Wiggins, B. G., Aliazis, K., Davies, S. P., Hirschfield, G. M., Lalor, P. F., Reynolds, G. M., & Stamataki, Z. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6931-9_14 · Cited by 1
Lu, W., Xu, J., Wang, K., Chen, Y., Cherubini, A., Valenti, L. V. C., Zheng, S., & Liu, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1954491
Single-cell transcriptome atlas revealed liver immune features in biliary atresia
刘雪来, Liu, Z., Wang, H., Chen, Y., Ye, M., Xu, L., Geng, Y., Cui, X., & He, F. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1995199
Beyond Exhaustion: The RNA Regulatory Layer of Tissue‐Instructed T Cell Dysfunction
Andreata, F., Marasca, F., Bodega, B., & Iannacone, M. (2026) · European Journal of Immunology · doi:10.1002/eji.70286
Self-citationLi, X.-J., Zhang, N., Zhang, Q., Chen, R., & Yu, G. (2026) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-026-05686-z
Intravital Imaging as a Tool to Uncover Roles of Immune Cells in Chronic Liver Diseases
Rashid, M., Lee, W., & Kubes, P. (2026) · JHEP Reports · doi:10.1016/j.jhepr.2026.102030
Platelet-derived serotonin drives age-related lung pathology in SARS-CoV-2 infection
Marotta, D., Perucchini, C., Grillo, M., Fumagalli, V., Lucia, P. D., Rixon, J. A., Ravà, M., Giustini, L., Malpighi, C., D’Uonnolo, G., et al. (2026) · Science Immunology · doi:10.1126/sciimmunol.aec9853
Self-citationYang, Z.-R., Qi, L.-K., Liu, D., Wang, W.-J., & Lu, J. (2026) · Medical Oncology · doi:10.1007/s12032-026-03362-y
“These T cells extend protrusions through endothelial fenestrations to probe hepatocytes for viral antigens, a diapedesis-independent immunosurveillance mechanism [ 34 ].”
Wang, F., Wang, L., Xu, Z. Y., 欧泽群, Yun, W., Haiying, Y., Fei, J., Song, J. H., Chen, Y., & Lv, K. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1899891
“Intravital imaging demonstrates that effector CD8 + T cells patrol hepatic sinusoids and engage infected hepatocytes in a non-migratory manner (62).”
Precursor Lesions in Hepatocellular Carcinogenesis
Roeb, E., & Schneider, M. (2026) · Visceral Medicine · doi:10.1159/000553489
“In a fibrotic liver, however, loss of fenestrae and sinusoidal remodelling impede this immunological patrolling, thereby compromising immune recognition of infected or transformed cells [63].”
Insights into oncovirus-driven tumor dynamics: a perspective from intravital imaging
Kim, H., Pyeon, D., & Park, S. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1830182
“…shown to be independent of selectins, β 2-and α 4-integrins, Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), Vascular Adhesion Protein-1 (VAP-1), Guanine nucleotide-binding protein G(i) subunit alpha (G α i)-coupled chemokine receptors, or even antigen recognition (Guidotti et al., 2015).”
Shi, Y., Xie, Y.-C., Chen, Y., Guo, X., Yang, L., Song, X., Feng, F., Lu, J.-H., & Dai, E.-H. (2026) · Virus Research · doi:10.1016/j.virusres.2026.199760
“(Guidotti et al., 2015; Ferrari et al., 2017) A study found a positive correlation between HBV RNA and ALT levels (r = 0.263, = 0.001).”
InfluentialTwo-Photon Microscopy in Biological Imaging: Current Uses and Evolving Potential
Bu, Q., Gu, Y., Wang, X., Yuan, S., Song, K., & Zhang, X. (2026) · Photonics · doi:10.3390/photonics13060519 · Cited by 2
Lin, C.-I., Chiu, Y.-W., Yen, M.-S., Wang, Y., Wu, Y.-Y., & Chuang, Y.-H. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-012460 · Cited by 2
“6 In murine HCC models, the absence of CD8 + T cells accelerates tumor growth, 7 while in human HCC, a high presence of tumor antigen-specific CD8 + TILs correlates with improved survival and reduced disease progression.”
Yang, H., Yang, Y., Tang, C., Zhou, Y., Yu, W., Huang, Q., Wang, H., Wu, D., Quan, W., Wang, J., et al. (2026) · Viruses · doi:10.3390/v18020201 · Cited by 1
“Stimulated CD8 + T cells can migrate within liver sinusoids and recognize infected hepatocytes or endothelial cells [42].”
O'Connor, J., McNamara, H., Cai, Y., Coupland, L., Gardiner, E., Parish, C., McMorran, B., Ganusov, V., & Cockburn, I. (2021) · bioRxiv · doi:10.1101/2021.11.09.467964
“Subsequent work has shown that platelets act as 69 landing pads for CD8+ T cells to dock on prior to establishing residence in the hepatic 70 sinusoids [16].”
BackgroundResultInfluentialSalivary gland macrophages assist tissue-resident CD8+ T cell immune surveillancePreprint
Stolp, B., Thelen, F., Ficht, X., Altenburger, L., Ruef, N., Inavalli, V. V. G. K., Germann, P., Page, N., Moalli, F., Raimondi, A., et al. (2019) · bioRxiv · doi:10.1101/723791
“After confocal image acquisition, the coverslips were gently removed and sections 742 adherent to the slide were processed for TEM as described (86).”
MethodSelf-citationAbrignani, S., Neddermann, P., Houghton, M., & Francesco, R. D. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-35761-6.00026-2 · Cited by 1
Mechanisms of Adaptive Immunity to Plasmodium Liver-Stage Infection: The Known and Unknown
Urban, S. L., Doll, K. L., & Harty, J. T. (2017) · Springer eBooks · doi:10.1007/978-3-319-45210-4_2
“Recent IVM data suggests that hepatitis B virus-specific in vitro-generated effector CD8 T cells in the liver are localized in the vasculature and do not require migration into liver parenchymal tissue to kill infected hepatocytes [75].”
BackgroundHepatitis B Virus Immunopathogenesis
Iannacone, M., & Guidotti, L. G. (2015) · Molecular and translational medicine · doi:10.1007/978-3-319-22330-8_4 · Cited by 3
“Recent data indicate that selectins, β2- and α4-integrins, platelet endothelial cell adhesion molecule (PECAM)-1, vascular adhesion protein (VAP)-1, and Gαicoupled chemokine receptors (all previously thought to be variably relevant for leukocyte traffi cking in other organs) are not required for the hepatic homing of…”
BackgroundInfluentialSelf-citationCD8 T cell dependent and independent immunity against Plasmodium following vaccination
Kanne, D., & Lee, K. (2016) · doi:10.17077/etd.yrl192w6
“Recent IVM data suggests that hepatitis B virus-specific in vitro generated effector CD8 T cells in the liver are localized in the vasculature and do not require migration into liver parenchymal tissue to kill infected hepatocytes (245).”
Background
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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