Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

Linda Diehl, Anna Schurich, Regina Grochtmann, Silke Hegenbarth, Lieping Chen, Percy A. Knolle

Research output: Contribution to journalArticle

Abstract

Liver sinusoidal endothelial cells (LSEC) are unique organ-resident antigen-presenting cells capable of cross-presentation and subsequent tolerization of naïve CD8+ T cells. We investigated the molecular mechanisms underlying this tolerance induction in naive CD8 + T cells. MHC class I-restricted antigen presentation by LSEC led to initial stimulation of naïve CD8+ T cells, which up-regulated CD69, CD25, CD44, and programmed death (PD)-1 and proliferated similar to dendritic cell (DC)-activated CD8+ T cells. Importantly, cognate interaction with naïve CD8+ T cells triggered increased expression of co-inhibitory B7-H1 but not co-stimulatory CD80/86 molecules exclusively on LSEC but not DC. This matured phenotype of B7-H1high CD80/86low was critical for induction of CD8+ T cell tolerance by LSEC: B7-H1-deficient LSEC, that failed to interact with PD-1 on stimulated T cells, were incapable of inducing CD8+ T cell tolerance. Moreover, increased costimulation via CD28 interfered with tolerance induction, indicating that the noninducible low expression levels of CD80/86 on LSEC supported B7-H1-dependent tolerance induction. LSEC-tolerized CD8+ T cells had a distinctive phenotype from naïve and activated T cells with CD25low, CD44high, CD62Lhigh. They also expressed the homeostatic cytokine receptors CD127, CD122, and high levels of Bcl-2, indicating survival rather than deletion of tolerant CD8+ T cells. On adoptive transfer into congenic animals, tolerized CD8+ T cells failed to show specific cytotoxicity in vivo. Conclusion: Cognate interaction of LSEC with naïve CD8+ T cells elicits a unique tolerogenic maturation of LSEC and permissiveness of T cells for tolerogenic signals, demonstrating that LSEC-induced tolerance is an active and dynamic process.

Original languageEnglish (US)
Pages (from-to)296-305
Number of pages10
JournalHepatology
Volume47
Issue number1
DOIs
StatePublished - Jan 2008

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Endothelial Cells
T-Lymphocytes
Liver
Dendritic Cells
Congenic Animals
Permissiveness
Cross-Priming
Phenotype
Histocompatibility Antigens Class I
Cytokine Receptors
Adoptive Transfer
Antigen Presentation
Antigen-Presenting Cells

ASJC Scopus subject areas

  • Hepatology

Cite this

Diehl, L., Schurich, A., Grochtmann, R., Hegenbarth, S., Chen, L., & Knolle, P. A. (2008). Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology, 47(1), 296-305. https://doi.org/10.1002/hep.21965

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. / Diehl, Linda; Schurich, Anna; Grochtmann, Regina; Hegenbarth, Silke; Chen, Lieping; Knolle, Percy A.

In: Hepatology, Vol. 47, No. 1, 01.2008, p. 296-305.

Research output: Contribution to journalArticle

Diehl, L, Schurich, A, Grochtmann, R, Hegenbarth, S, Chen, L & Knolle, PA 2008, 'Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance', Hepatology, vol. 47, no. 1, pp. 296-305. https://doi.org/10.1002/hep.21965
Diehl, Linda ; Schurich, Anna ; Grochtmann, Regina ; Hegenbarth, Silke ; Chen, Lieping ; Knolle, Percy A. / Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. In: Hepatology. 2008 ; Vol. 47, No. 1. pp. 296-305.
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AU - Chen, Lieping

AU - Knolle, Percy A.

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N2 - Liver sinusoidal endothelial cells (LSEC) are unique organ-resident antigen-presenting cells capable of cross-presentation and subsequent tolerization of naïve CD8+ T cells. We investigated the molecular mechanisms underlying this tolerance induction in naive CD8 + T cells. MHC class I-restricted antigen presentation by LSEC led to initial stimulation of naïve CD8+ T cells, which up-regulated CD69, CD25, CD44, and programmed death (PD)-1 and proliferated similar to dendritic cell (DC)-activated CD8+ T cells. Importantly, cognate interaction with naïve CD8+ T cells triggered increased expression of co-inhibitory B7-H1 but not co-stimulatory CD80/86 molecules exclusively on LSEC but not DC. This matured phenotype of B7-H1high CD80/86low was critical for induction of CD8+ T cell tolerance by LSEC: B7-H1-deficient LSEC, that failed to interact with PD-1 on stimulated T cells, were incapable of inducing CD8+ T cell tolerance. Moreover, increased costimulation via CD28 interfered with tolerance induction, indicating that the noninducible low expression levels of CD80/86 on LSEC supported B7-H1-dependent tolerance induction. LSEC-tolerized CD8+ T cells had a distinctive phenotype from naïve and activated T cells with CD25low, CD44high, CD62Lhigh. They also expressed the homeostatic cytokine receptors CD127, CD122, and high levels of Bcl-2, indicating survival rather than deletion of tolerant CD8+ T cells. On adoptive transfer into congenic animals, tolerized CD8+ T cells failed to show specific cytotoxicity in vivo. Conclusion: Cognate interaction of LSEC with naïve CD8+ T cells elicits a unique tolerogenic maturation of LSEC and permissiveness of T cells for tolerogenic signals, demonstrating that LSEC-induced tolerance is an active and dynamic process.

AB - Liver sinusoidal endothelial cells (LSEC) are unique organ-resident antigen-presenting cells capable of cross-presentation and subsequent tolerization of naïve CD8+ T cells. We investigated the molecular mechanisms underlying this tolerance induction in naive CD8 + T cells. MHC class I-restricted antigen presentation by LSEC led to initial stimulation of naïve CD8+ T cells, which up-regulated CD69, CD25, CD44, and programmed death (PD)-1 and proliferated similar to dendritic cell (DC)-activated CD8+ T cells. Importantly, cognate interaction with naïve CD8+ T cells triggered increased expression of co-inhibitory B7-H1 but not co-stimulatory CD80/86 molecules exclusively on LSEC but not DC. This matured phenotype of B7-H1high CD80/86low was critical for induction of CD8+ T cell tolerance by LSEC: B7-H1-deficient LSEC, that failed to interact with PD-1 on stimulated T cells, were incapable of inducing CD8+ T cell tolerance. Moreover, increased costimulation via CD28 interfered with tolerance induction, indicating that the noninducible low expression levels of CD80/86 on LSEC supported B7-H1-dependent tolerance induction. LSEC-tolerized CD8+ T cells had a distinctive phenotype from naïve and activated T cells with CD25low, CD44high, CD62Lhigh. They also expressed the homeostatic cytokine receptors CD127, CD122, and high levels of Bcl-2, indicating survival rather than deletion of tolerant CD8+ T cells. On adoptive transfer into congenic animals, tolerized CD8+ T cells failed to show specific cytotoxicity in vivo. Conclusion: Cognate interaction of LSEC with naïve CD8+ T cells elicits a unique tolerogenic maturation of LSEC and permissiveness of T cells for tolerogenic signals, demonstrating that LSEC-induced tolerance is an active and dynamic process.

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