title: Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells.
abstract: 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.
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Martina
authors.initials: M
authors.lastname: Berg
authors.forename: Dirk
authors.initials: D
authors.lastname: Stabenow
authors.forename: Jan
authors.initials: J
authors.lastname: Böttcher
authors.forename: Michaela
authors.initials: M
authors.lastname: Kern
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Schild
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Verena
authors.initials: V
authors.lastname: Schuette
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D045142:Cross-Priming / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D042783:Endothelial Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D008099:Liver / Q000166:cytology* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000276:immunology
chemical_list: D010047:Ovalbumin