Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance.
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-H1(high) CD80/86(low) 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 CD25(low), CD44(high), CD62L(high). 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.


CONCLUSIONS
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.
Diehl
Linda
L
Institute for Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany.
Schurich
Anna
A
Grochtmann
Regina
R
Hegenbarth
Silke
S
Chen
Lieping
L
Knolle
Percy A
PA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D007108:Immune Tolerance / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000502:physiology
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor