title: Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system.
abstract: Hapten sensitization through UV-exposed skin induces tolerance that is mediated via the induction of hapten-specific T suppressor cells. However, the detailed mechanisms underlying tolerance induction remain unclear to date. We show here that the apoptosis-related surface Ag Fas (APO-1, CD95) and its ligand, Fas ligand (FasL) are critically involved, since Fas-deficient lpr mice and FasL-deficient gld mice do not develop UV-induced tolerance. Adoptive transfer experiments revealed that the mediation of tolerance does not require the expression of Fas or FasL by the T suppressor cells but does require the expression of both molecules by the cells of mice receiving the T suppressor cells. To identify the mechanisms involved, the effect of suppressor cells on Ag-presenting dendritic cells (DC) was studied. Coincubation of hapten-pulsed DC with T cells that were obtained from UV-tolerized mice resulted in an enhanced death rate of DC, and this cell death was dependent upon Fas expression. The addition of IL-12, which recently was found to break established tolerance in vivo, prevented DC death. Moreover, IL-12 did not only rescue DC from T suppressor cell-induced death but also from apoptosis induced by rFasL, suggesting that IL-12 may interfere with the Fas/FasL system. Together, these data indicate a crucial role for the Fas/FasL system in UV-induced tolerance, and suggest that UV-induced T suppressor cells may act by inducing the cell death of APCs via the Fas pathway. The ability of IL-12 to break established tolerance may be due to the prevention of DC death induced by T suppressor cells.
authors.affiliation: Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University Münster, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schwarz
authors.forename: S
authors.initials: S
authors.lastname: Grabbe
authors.forename: K
authors.initials: K
authors.lastname: Grosse-Heitmeyer
authors.forename: B
authors.initials: B
authors.lastname: Roters
authors.forename: H
authors.initials: H
authors.lastname: Riemann
authors.forename: T A
authors.initials: TA
authors.lastname: Luger
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: T
authors.initials: T
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein; D006241:Haptens / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology* / Q000528:radiation effects*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D013601:T-Lymphocytes / Q000276:immunology; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000276:immunology*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006241:Haptens; D008562:Membrane Glycoproteins; D019014:fas Receptor