Immunosurveillance of the Liver by Intravascular Effector CD8 + T Cells
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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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Effector CD8+ T cells can extend cellular protrusions through sinusoidal fenestrae and make contact with the hepatocyte membrane, creating a synapse-like process.
“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]
Reducing the access of T cells to the sinusoidal fenestrae inhibits antigen recognition.
“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]
In a transgenic mouse model of HBV infection, effector CD8+ T cells arrest within the sinusoids by docking on platelets adhered to LSECs, crawl along sinusoids, and extend cytoplasmic protrusions through LSEC fenestrae to search for antigens on hepatocytes.
“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-citationMonoclonal antibodies to CD44 and their influence on hyaluronan recognition
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InfluentialIn Vivo Flow Mapping in Complex Vessel Networks by Single Image Correlation
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Migrating Platelets Are Mechano-scavengers that Collect and Bundle Bacteria.
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Self-citationDynamics and genomic landscape of CD8+ T cells undergoing hepatic priming
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Self-citationSpatial reconstruction of immune niches by combining photoactivatable reporters and scRNA-seq
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Self-citationBlood coagulation in immunothrombosis—At the frontline of intravascular immunity
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Immunological functions of liver sinusoidal endothelial cells
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The evolving role of liver sinusoidal endothelial cells in liver health and disease
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“The highly specialized, fenestrated morphology of LSECs then allows these CD8+ T cells to extend processes through the fenestrae to survey hepatocytes for viral infection and exert their effector function(29).”
Targeting Innate and Adaptive Immune Responses to Cure Chronic HBV Infection
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Measuring and interpreting platelet-leukocyte aggregates
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“This is substantial for recruitment of virus-specific CD8 T cells causing hepatocellular injury (53,54) potentially via CD40L (100).”
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Host-virus interactions in hepatitis B virus infection
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“The extent of hepatocellular injury wasmonitored bymeasuring serum alanine aminotransferase (sALT) activity atmultiple time points after treatment, as previously described (Guidotti et al., 2015).”
BackgroundMethodInfluentialSelf-citationPlatelets: No longer bystanders in liver disease
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Immunofluorescence identifies distinct subsets of endothelial cells in the human liver
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“LSEC may play a pivotal role in tolerization via antigen presentation to CD8 + T cells 40 and capillarization of LSEC in animal models of cirrhotic liver disease contributes to immune dysfunction 41 .”
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“Interestingly, a negative role of a dense ECM on T cell immune surveillance was recently reported during liver fibrosis (29).”
BackgroundMechanisms of organ fibrosis: Emerging concepts and implications for novel treatment strategies
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Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity.
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“Thus, we turned to a syngeneic model, in which T cell receptor (TCR) transgenic CD8+ Tn cells specific for the hepatitis B virus epitope Cor93 (45) were qPCR (C; n = 3–5 HD in n = 2–3 exp.”
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Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets
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“Eradicating liver endothelial cell fenestrations by an established technique of treating the mice with highly diluted arsenic in their drinkingwater (Guidotti et al., 2015; Straub et al., 2007) did not significantly impact the platelet count, indicating that hepatocytic microvilli are not a major…”
BackgroundInfluentialNiches for the Long-Term Maintenance of Tissue-Resident Memory T Cells
Takamura, S. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01214 · Cited by 123 · see citing works
“Fenestrated sinusoidal endothelium also enables the direct surveillance of hepatocytes by circulating T cells (231).”
BackgroundThe Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver
Wilkinson, A. L., Qurashi, M., & Shetty, S. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00990 · Cited by 121 · see citing works
Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates
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Self-citationNatural killer cells and liver fibrosis
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“Cytotoxic T cells may overcome the endothelial barrier and probe antigens on subsinusoidal cells by extending cytoplasmic protrusions through sinusoidal endothelial fenestrae (68).”
BackgroundInverso, D., Shi, J., Lee, K. H., Jakab, M., Ben-Moshe, S., Kulkarni, S. R., Schneider, M., Wang, G., Komeili, M., Vélez, P. A., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.05.001 · Cited by 114 · see citing works
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“Thus, antigen experienced CD8+ effector T cells may be incapable of recognizing transformed hepatocytes in the setting of fibrosis despite previous antigen presentation and activation [65].”
BackgroundPlatelet-Leukocyte Interplay in Cancer Development and Progression
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“These immune surveillance processes might get disturbed by liver fibrosis [53].”
BackgroundInflammatory monocytes hinder antiviral B cell responses
Sammicheli, S., Kuka, M., Lucia, P. D., de Oya, N. J., Giovanni, M. D., Fioravanti, J., Cristofani, C., Maganuco, C. G., Fallet, B., Ganzer, L., et al. (2016) · Science Immunology · doi:10.1126/sciimmunol.aah6789 · Cited by 116 · see citing works
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Platelets: Orchestrators of immunity in host defense and beyond.
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Human circulating and tissue-resident memory CD8+ T cells
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Understanding, predicting and achieving liver transplant tolerance: from bench to bedside
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A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection
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“LSECs are known as tolerogenic antigen-(cross)presenting cells which induce dysfunction in naive CD8 T cells 43 but LSECs failed to cross-present HB core antigen to HB core CD8 T cells 7 (Extended Data Fig.”
InfluentialSelf-citationEmbrionary way to create a fatty liver in portal hypertension
Kotlarz, D., Gürkan, Ö. E., Haskologlu, Z. S., Ekinci, O., Unlusoy, A. A., Kaya, N. G., Puchalka, J., Klein, C., & Dalgıç, B. (2017) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v8.i2.39 · Cited by 97 · see citing works
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Self-citationThe identity of human tissue-emigrant CD8+ T cells
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The gut microbiota–bile acid axis: A potential therapeutic target for liver fibrosis
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“R e s t o r i n g t h e no rma l gu t m i c r ob i o t a v i a f e c a l transplantation can reduce liver fibrosis via remodeling of the intrahepatic TCR IR, a reduction in B cells, and an increase in CD8+ T cells (Novobrantseva et al., 2005; Guidotti et al., 2015; Liang et al., 2020).”
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Angiocrine signaling in sinusoidal homeostasis and liver diseases
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Angiodiversity and organotypic functions of sinusoidal endothelial cells
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“Correspondingly, EC from the fetal liver were found to express PLVAP and VEGFR2, reflecting the oncofetal nature of HCC angiogenesis.”
BackgroundInfluentialActivated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2
Constantinescu-Bercu, A., Grassi, L., Frontini, M., Salles-Crawley, I. I., Woollard, K., & Crawley, J. T. (2018) · bioRxiv · doi:10.7554/elife.53353 · Cited by 84 · see citing works
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“confirmed that by adhering to platelets in hepatic blood sinuses, intrahepatic CD8+ effector T-cells recognize and kill cancer cells, which can be damaged by the liver fibration.(9) Also, studies in liver cancer patients on the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), which are two…”
BackgroundPlatelets in chronic liver disease, from bench to bedside
Ramadori, P., Klag, T., Malek, N. P., & Heikenwälder, M. F. (2019) · JHEP Reports · doi:10.1016/j.jhepr.2019.10.001 · Cited by 90 · see citing works
The role of hyaluronan in the pathobiology and treatment of respiratory disease
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“, endothelia (52, 83, 87, 91) and platelets (1, 36, 75).”
Immune surveillance of the liver by T cells
Ficht, X., & Iannacone, M. (2020) · Science immunology · doi:10.1126/sciimmunol.aba2351 · Cited by 74 · see citing works
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Self-citationHBV-Specific CD8+ T-Cell Tolerance in the Liver
Baudi, I., Kawashima, K., & Isogawa, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.721975 · Cited by 76 · see citing works
“Intravital imaging analysis revealed that HBV-specific CD8+ T cells were able to recognize HBV expressing hepatocytes while they were still in the sinusoid (73).”
BackgroundSelf-citationMicrofluidic-based vascularized microphysiological systems
Lee, S., Ko, J., Park, D., Lee, B., Chung, M., Lee, Y., & Jeon, N. L. (2018) · Lab on a Chip · doi:10.1039/c8lc00285a · Cited by 92 · see citing works
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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…”
BackgroundPlatelet-mediated modulation of adaptive immunity.
Iannacone, M. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.10.008 · Cited by 67
Self-citationThe role of liver sinusoidal cells in local hepatic immune surveillance
Wohlleber, D., & Knolle, P. A. (2016) · Clinical & Translational Immunology · doi:10.1038/cti.2016.74 · Cited by 64 · see citing works
Lurje, I., Werner, W., Mohr, R. U., Roderburg, C., Tacke, F., & Hammerich, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.650486 · Cited by 75 · see citing works
Liver sampling: a vital window into HBV pathogenesis on the path to functional cure
Gill, U. S., Pallett, L. J., Kennedy, P. T. F., & Maini, M. K. (2018) · Gut · doi:10.1136/gutjnl-2017-314873 · Cited by 57 · see citing works
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Recording the wild lives of immune cells
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The Paradoxical Role of NKG2D in Cancer Immunity
Sheppard, S., Ferry, A., Guedes, J., & Guerra, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01808 · Cited by 61 · see citing works
“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
Chen, Y., Hu, H., Yuan, X., Fan, X., & Zhang, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.896752 · Cited by 61 · see citing works
“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).”
BackgroundCheckpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection
Hoogeveen, R. C., & Boonstra, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00401 · Cited by 61 · see citing works
Effector CD8+ T cell-derived interleukin-10 enhances acute liver immunopathology
Fioravanti, J., Lucia, P. D., Magini, D., Moalli, F., Boni, C., Benechet, A. P., Fumagalli, V., Inverso, D., Vecchi, A., Fiocchi, A., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.04.020 · Cited by 57 · see citing works
“Generation of CD8 TE and adoptive transfer In vitro generation of CD8 TE was performed as described.(16,26) Briefly, splenocytes from Cor93 or Env28 TCR transgenic mice were incubated with 10 lg/ml of Cor93-100 (K; MGLKFRQL) or Env28-39 (L; IPQSLDSWWTSL) peptides (Primm), respectively, at 37 C for 1 h, washed, and cul…”
InfluentialSelf-citationDavies, S. P., Reynolds, G. M., & Stamataki, Z. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00044 · Cited by 61 · see citing works
“Fenestrations in the sinusoids allow hepatocytes access to solutes and immune cells reaching through the fenestrations from the circulation (2, 3), but prevent unregulated migration of immune cells to the parenchyma (4).”
BackgroundNishio, A., Bolte, F. J., Takeda, K., Park, N., Yu, Z., Park, H., Valdez, K., Ghany, M. G., & Rehermann, B. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aba6322 · Cited by 54 · see citing works
Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection
Fumagalli, V., Lucia, P. D., Venzin, V., Bono, E., Jordan, R., Frey, C., Delaney, W., Chisari, F., Guidotti, L., & Iannacone, M. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20200298 · Cited by 53
Self-citationThe liver as a central "hub" of the immune system: pathophysiological implications
Ronca, V., Gerussi, A., Collins, P., Parente, A., Oo, Y. H., & Invernizzi, P. (2025) · Physiological Reviews · doi:10.1152/physrev.00004.2023 · Cited by 59 · see citing works
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“However, viral infection likely interfered with the ability of platelets to maintain the integrity of the vascular endothelium by plugging up holes in the vascular endothelium (50), thereby encouraging further enhanced vascular leakage.”
BackgroundSelf-citationPatten, D., Wilson, G., Bailey, D., Shaw, R., Jalkanen, S., Salmi, M., Rot, A., Weston, C. J., Adams, D., & Shetty, S. (2016) · Hepatology · doi:10.1002/hep.28879 · Cited by 52 · see citing works
“occurs within the hepatic sinusoidal channels in contrast to the post-capillary venules as seen in most other organs(8, 9).”
ResultProtective immunity to liver-stage malaria
Holz, L. E., Fernandez-Ruiz, D., & Heath, W. (2016) · Clinical & Translational Immunology · doi:10.1038/cti.2016.60 · Cited by 52 · see citing works
The liver as an immunological barrier redefined by single‐cell analysis
Stamataki, Z., & Swadling, L. (2020) · Immunology · doi:10.1111/imm.13193 · Cited by 48 · see citing works
Therapeutic potential of co-signaling receptor modulation in hepatitis B
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Self-citationT Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System
Huang, W., Easom, N. J. W., Tang, X.-Z. E., Gill, U. S., Singh, H., Robertson, F. P., Chang, C., Trowsdale, J., Davidson, B. R., Rosenberg, W. M., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601313 · Cited by 44 · see citing works
“first encounter HBV-specific T cells (10, 57), a large fraction of which expressed NKG2DL upon stimulation with their cognate peptide.”
BackgroundGut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD
Termite, F., Archilei, S., D’Ambrosio, F., Petrucci, L., Viceconti, N., Iaccarino, R., Liguori, A., Gasbarrini, A., & Miele, L. (2025) · Antioxidants · doi:10.3390/antiox14010056 · Cited by 46 · see citing works
Hepatocytes Delete Regulatory T Cells by Enclysis, a CD4+ T Cell Engulfment Process
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Self-citationMultiphoton intravital microscopy of rodents
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Staying local-antigen presentation in the liver
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Immune-metabolic interactions in homeostasis and the progression to NASH.
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Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists
Bartsch, L., Damasio, M., Subudhi, S., & Drescher, H. K. (2020) · Cells · doi:10.3390/cells9112457 · Cited by 41 · see citing works
“Additionally, liver TRM cells express other adhesions and functional molecules, such as CD103, CD49a and CD44, to enable trafficking within the liver sinusoids and liver tissue [4].”
BackgroundTill Death Do Us Part—The Multifaceted Role of Platelets in Liver Diseases
Mußbacher, M., Brunnthaler, L., Panhuber, A., Starlinger, P. P., & Assinger, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063113 · Cited by 41 · see citing works
“during a hepatitis virus infection [52].”
Hyaluronan and Its Receptors as Regulatory Molecules of the Endothelial Interface
Queisser, K., Mellema, R. A., & Petrey, A. C. (2020) · Journal of Histochemistry and Cytochemistry · doi:10.1369/0022155420954296 · Cited by 40
Viral hepatitis, inflammation, and cancer: A lesson for autoimmunity
Piconese, S., Cammarata, I., & Barnaba, V. (2018) · Journal of Autoimmunity · doi:10.1016/j.jaut.2018.10.021 · Cited by 40 · see citing works
Lefebvre, M. N., Surette, F. A., Anthony, S. M., Vijay, R., Jensen, I. J., Pewe, L. L., Hancox, L. S., Budimir, N., van de Wall, S., Urban, S. L., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109956 · Cited by 37 · see citing works
“…(Lee et al., 2010; Peng et al., 2016); type I IFN signaling (data not shown), which mediates leukocyte trafficking (Liehl et al., 2014); and platelets (Figure 5F), which form intra-sinusoidal clusters that effector CD8 T cells utilize to localize to the infected liver (Guidotti et al., 2015).”
BackgroundInfluentialde Krijger, M., Wildenberg, M. E., de Jonge, W. J., & Ponsioen, C. Y. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.05.006 · Cited by 42 · see citing works
“6).(49, 51) Involvement of secreted chemokines including CXC-chemokine ligand 9 (CXCL9), -10 and -11 leads to attraction of”
BackgroundLee, T.-Y., Hsu, Y.-C., Ho, H., Lin, J.-T., Chen, Y.-J., & Wu, C.-Y. (2023) · EClinicalMedicine · doi:10.1016/j.eclinm.2023.102065 · Cited by 38 · see citing works
- 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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