Dynamic Regulation of CD8 T Cell Tolerance Induction by Liver Sinusoidal Endothelial Cells
Open accessAbstract
Cross-presentation of soluble Ag on MHC class I molecules to naive CD8 T cells by liver sinusoidal endothelial cells (LSECs) leads to induction of T cell tolerance that requires interaction between coinhibitory B7-H1 on LSECs and programmed cell death-1 on CD8 T cells. In this study, we investigate whether cross-presentation of high as well as low Ag concentrations allowed for LSEC-induced tolerance. Ag concentration directly correlated with the cross-presentation capacity of murine LSECs and thus strength of TCR stimulation. Although LSEC cross-presentation at low-Ag concentrations resulted in tolerance, they induced differentiation into effector T cells (CTL) at high-Ag concentrations. CTL differentiation under these conditions was not caused by increased expression of costimulatory CD80/86 on cross-presenting LSECs but was determined by early IL-2 release from naive CD8 T cells. B7-H1 signals from LSECs and TCR avidity reciprocally controlled early T cell release of IL-2 and CTL differentiation. B7-H1 expression directly correlated with cross-presentation at low- but not high-Ag concentrations, indicating an imbalance between TCR and coinhibitory signals regulating T cell release of IL-2. Exogenous IL-2 overrode coinhibitory B7-H1–mediated signals by LSECs and induced full CTL differentiation. Our results imply that LSEC-mediated T cell tolerance can be broken in situations where T cells bearing high-avidity TCR encounter LSECs cross-presenting high numbers of cognate MHC class I peptide molecules, such as during viral infection of the liver. Furthermore, we attribute a novel costimulatory function to IL-2 acting in a T cell autonomous fashion to promote local induction of immunity in the liver even in the absence of CD80/86 costimulation.
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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 [28]
The Abstract and Discussion address CD8 T-cell responses to antigen presentation by liver sinusoidal endothelial cells, not lymphocyte infiltration in experimental MASH. Searches for MASH, steatohepatitis, B-cell infiltration, and choline-deficient high-fat diet found no passage addressing the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredRag1-/- mice were also protected from hepatic steatosis by a mechanism that seemed to occur independently of metabolic disturbances, indicating that T cells directly modulate lipid handling by hepatocytes.
“Interestingly, these mice were also protected from hepatic steatosis by a mechanism that seemed to occur independently of metabolic disturbances, indicating that T cells directly modulate lipid handling by hepatocytes (28).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [28]
The Mice section lists the strains used but does not mention Rag1-/- mice. The Discussion addresses CD8 T-cell tolerance and immunity induced by liver sinusoidal endothelial cells, not hepatic steatosis or hepatocyte lipid handling. Searches for Rag1, steatosis, and metabolic disturbances found no passage addressing the claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredRag1-/- mice which lack mature T and B cells are protected from lobular inflammation and liver cell injury induced by feeding a choline-deficient high fat diet.
“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 [28]
The Mice section lists the strains used but does not mention Rag1-deficient mice. The Discussion addresses CD8 T-cell responses to antigen presentation, not diet-induced lobular inflammation or liver-cell injury. Searches for Rag1, a choline-deficient high-fat diet, and protection from liver injury found no passage supporting the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- Authors
- Schurich, A., Berg, M., Stabenow, D., Böttcher, J., Kern, M., Schild, H.-J., Kurts, C., Schuette, V., Burgdorf, S., Diehl, L., Limmer, A., & Knolle, P. A.
- Affiliations
- University of Bonn (DE)
- Institute of Immunology, University of Mainz , Mainz,
- Corresponding author
- Schurich, Anna
- Berg, Martina
- Stabenow, Dirk
- Kern, Michaela
- Kurts, Christian
- Schuette, Verena
- Burgdorf, Sven
- Diehl, Linda
- Limmer, Andreas
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04
- Volume
- 184
- Issue
- 8
- Pages
- 4107-4114
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2166333477
- Cited by
- 124
- References
- 34
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 11 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 11 · 2019: 3 · 2018: 16 · 2017: 8 · 2016: 10 · 2015: 5 · 2014: 8 · 2013: 4 · 2012: 7
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 704, SFB 670)
- Rheinische Friedrich-Wilhelms-Universität Bonn (SFB 704)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- liver sinusoidal endothelial cells, CD8+ T cell tolerance, cross-presentation, PD-L1, PD-1, interleukin-2, T cell receptor avidity, costimulation, CD80/86, liver immunity, MHC class I
- MeSH terms
- Animals, Cells, Cultured, Cytotoxicity Tests, Immunologic, Immune Tolerance, Liver, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Transgenic, Ovalbumin, Resting Phase, Cell Cycle, Antigen Presentation, Mice, Knockout, CD8-Positive T-Lymphocytes, Coculture Techniques, Endothelial Cells, Cross-Priming, Mice
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