Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance
Open accessAbstract
Myeloid antigen-presenting cells (APC) are known to cross-present exogenous antigen on major histocompatibility class I molecules to CD8+ T cells and thereby induce protective immunity against infecting microorganisms. Here we report that liver sinusoidal endothelial cells (LSEC) are organ-resident, non-myeloid APC capable of cross-presenting soluble exogenous antigen to CD8+ T cells. Though LSEC employ similar molecular mechanisms for cross-presentation as dendritic cells, the outcome of cross-presentation by LSEC is CD8+ T cell tolerance rather than immunity. As uptake of circulating antigens into LSEC occurs efficiently in vivo, it is likely that cross-presentation by LSEC contributes to CD8+ T cell tolerance observed in situations where soluble antigen is present in the circulation.
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Hepatic infiltration by CD4+ T, CD8+ T and B lymphocytes is evident in different experimental models of MASH.
“Hepatic infiltration by CD4+ T, CD8+ T and B lymphocytes is evident in different experimental models of MASH (28-30), while Rag1 -/mice which lack mature T and B cells are protected from lobular inflammation and liver cell injury induced by feeding a cholinedeficient high fat diet (28).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [29]
The LSEC cross-presentation and LSEC Transplantation sections describe antigen-specific CD8+ T-cell responses in the liver, not lymphocyte infiltration in experimental MASH. Searches for MASH, steatohepatitis, CD4+ and B-cell infiltration, and choline-deficient high-fat diets found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.76)
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Microanatomy of the liver immune system
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“…cells to induce peripheral CD8 + T cell tolerance is not unique to LECs and FRCs. Liver sinusoidal endothelial cells (LSECs) are considered critical for tolerance to food antigens, as they mount CD8 + deletional tolerance against exogenous antigens coming directly from the gut (68, 69).”
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BackgroundHepatic Immune Regulation and Its Involvement in Viral Hepatitis Infection
Knolle, P. A., & Thimme, R. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.12.036 · Cited by 206 · see citing works
Self-citationGeijtenbeek, T., Groot, P. C., Nolte, M., van Vliet, S. V., Gangaram-Panday, S., van Duijnhoven, G. V., Kraal, G., van Oosterhout, A., & van Kooyk, Y. (2002) · Blood · doi:10.1182/blood-2002-04-1044 · Cited by 208 · see citing works
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PLGA microspheres for improved antigen delivery to dendritic cells as cellular vaccines.
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Self-citationTargeting the tumour vasculature: from vessel destruction to promotion
Guelfi, S., Hodivala‐Dilke, K., & Bergers, G. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00736-0 · Cited by 195 · see citing works
Immunological functions of liver sinusoidal endothelial cells
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“In this regard, both liver sinusoidal endothelial cells (36) and hepatocytes (37) have been shown to be capable of presenting exogenous antigen, although the molecular details have yet to be completely elucidated.”
BackgroundBreaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
Holdener, M., Hintermann, E., Bayer, M., Rhode, A., Rodrigo, E., Hintereder, G., Johnson, E. F., Gonzalez, F. J., Pfeilschifter, J. M., Manns, M. P., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071859 · Cited by 194 · see citing works
“17 other cells such as liver sinusoidal endothelial cells are able to present exogenous antigens on class II MHC molecules as well (6).”
BackgroundKeenan, B. P., Fong, L. H., & Kelley, R. K. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0749-z · Cited by 219 · see citing works
The evolving role of liver sinusoidal endothelial cells in liver health and disease
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“Liver sinusoidal endothelial cells use the mannose receptor to take-up, process, and cross-present antigen via their major histocompatibility complex class I (MHC-I) receptors to CD8+ cytotoxic T cells(179).”
Carman, C. V., & Martinelli, R. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00603 · Cited by 208 · see citing works
“For example, LSEC promotes Ag-and coinhibitor-dependent CTL tolerance (102), suppression of CD4 proinflammatory Th1 and Th17 responses (31, 193, 194), and differentiation of CD4 Tregs (195).”
BackgroundUtilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy.
Silk, J., Hermans, I., Gileadi, U., Chong, T., Shepherd, D., Salio, M., Mathew, B., Schmidt, R., Lunt, S. J., Williams, K., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422046 · Cited by 184 · see citing works
“The type of APC involved in this process has not been ascertained, although some studies have shown Kupffer cells to be required (45), while others have indicated involvement of liver sinusoidal endothelial cells (LSECs) for the induction of both CD4+ and CD8+ T cell tolerance (46, 47).”
ResultNathwani, A. C., Davidoff, A. M., Hanawa, H., Hu, Y., Hoffer, F. A., Nikanorov, A. Y., Slaughter, C. A., Ng, C. Y., Zhou, J., Lozier, J. N., et al. (2002) · Blood · doi:10.1182/blood-2002-02-0589 · Cited by 164 · see citing works
Immunotherapy for hepatocellular carcinoma
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“These cell types include Kupffer cells (32, 33), sinusoidal endothelial cells (19, 20), hepatic stellate cells (34, 35), and hepatocytes (36, 37).”
BackgroundUhrig, A., Banafsche, R., Kremer, M., Hegenbarth, S., Hamann, A., Neurath, M., Gerken, G., Limmer, A., & Knolle, P. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0604332 · Cited by 176 · see citing works
Self-citationNeighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells.
Knolle, P., & Limmer, A. (2001) · Trends in immunology · doi:10.1016/s1471-4906(01)01957-3 · Cited by 172 · see citing works
Self-citationSas, Z., Cendrowicz, E., Weinhäuser, I., & Rygiel, T. P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073778 · Cited by 178 · see citing works
“In contrast to cross-presentation of antigens by professional antigen-presenting cells, LSECs lead to tolerance, rather than activation, of CD8+ T cells [42].”
ResultCarambia, A., Freund, B., Schwinge, D., Bruns†, O. T., Salmen, S. C., Ittrich, H., Reimer, R., Heine, M., Huber, S., Waurisch, C., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.01.006 · Cited by 180 · see citing works
“Indeed, LSECs are not only potent inducers of Tregs [14], but also potent suppressors of inflammatory CD4 and CD8 T cell effector responses [3-5,39,40].”
BackgroundLimmer, A., Ohl, J., Wingender, G., Berg, M., Jüngerkes, F., Schumak, B., Djandji, D., Scholz, K., Klevenz, A., Hegenbarth, S., et al. (2005) · European Journal of Immunology · doi:10.1002/eji.200526034 · Cited by 169 · see citing works
Self-citationOld Age and the Hepatic Sinusoid
Couteur, D. L., Warren, A., Cogger, V., Smedsrød, B., Sørensen, K., de Cabo, R., Fraser, R., & Mccuskey, R. (2008) · The Anatomical Record · doi:10.1002/ar.20661 · Cited by 169 · see citing works
“LSECs have a possible role in antigen presentation (Limmer et al., 2000) and may be involved in the development of immunotolerance by inducing apoptosis in lymphocytes (Karrar et al.”
BackgroundIshikawa, S., Sato, T., Abe, M., Nagai, S., Onai, N., Yoneyama, H., Zhang, Y.-Y., Suzuki, T., Hashimoto, S., Shirai, T., et al. (2001) · Journal of Experimental Medicine · doi:10.1084/jem.193.12.1393 · Cited by 169 · see citing works
Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation
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Antigen Presentation by Vascular Cells
Pober, J. S., Merola, J., Liu, R., & Manes, T. D. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01907 · Cited by 165 · see citing works
Herkel, J., Jagemann, B., Wiegard, C., Lazaro, J. F. G., Lueth, S., Kanzler, S., Blessing, M., Schmitt, E., & Lohse, A. W. (2003) · Hepatology · doi:10.1053/jhep.2003.50191 · Cited by 164 · see citing works
Microenvironmental Regulation of the Sinusoidal Endothelial Cell Phenotype In Vitro
March, S., Hui, E. E., Underhill, G. H., Khetani, S., & Bhatia, S. N. (2009) · Hepatology · doi:10.1002/hep.23085 · Cited by 163 · see citing works
“inducing CD8+T cell tolerance (4); and synthesize and release Factor VIII, a critical cofactor in the intrinsic coagulation pathway (5,6).”
Drug‐Induced Liver Injury: The Role of Drug Metabolism and Transport
Corsini, A., & Bortolini, M. (2013) · Journal of clinical pharmacology · doi:10.1002/jcph.23 · Cited by 162 · see citing works
- Authors
- Limmer, A., Ohl, J., Kurts, C., Ljunggren, H.-G., Reiss, Y., Groettrup, M., Momburg, F., Arnold, B., & Knolle, P. A.
- Affiliations
- Heidelberg University (DE)
- Medizinische Hochschule Hannover (DE)
- Karolinska Institutet (SE)
- Tel Aviv University (IL)
- Kantonsspital St. Gallen (CH)
- German Cancer Research Center (DE)
- Corresponding author
- Knolle, Percy A.
- ORCID
- Venue
- Nature Medicine
- Published
- 2000-12
- Volume
- 6
- Issue
- 12
- Pages
- 1348-1354
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1498929362
- Cited by
- 758
- References
- 0
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 26 · 2023: 33 · 2022: 25 · 2021: 41 · 2020: 37 · 2019: 20 · 2018: 30 · 2017: 21 · 2016: 19 · 2015: 32 · 2014: 28 · 2013: 36 · 2012: 25
- FWCI
- 8.27
- Type
- journal article
- Language
- en
- Open access
- green
- nbn-resolving.de
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft (SFB405)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- liver sinusoidal endothelial cells, cross-presentation, CD8+ T cell tolerance, exogenous antigen, MHC class I, dendritic cells, liver
- MeSH terms
- Animals, Antigen-Presenting Cells, Antigens, Bone Marrow Cells, Endothelium, Immune Tolerance, Liver, Mice, Inbred BALB C, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Transgenic, Ovalbumin, Antigen Presentation, CD8-Positive T-Lymphocytes, Mice
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