title: Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes.
abstract: Self-tolerance to melanocyte differentiation Ags limits the ability to generate therapeutic antimelanoma responses. However, the mechanisms responsible for CD8 T cell tolerance to these Ags are unknown. We have used a newly generated TCR-transgenic mouse to establish the basis of tolerance to one such Ag from tyrosinase. Despite expression of tyrosinase transcripts in the thymus, central deletion does not shape the tyrosinase-specific CD8 T cell repertoire. We demonstrate that this endogenously expressed melanocyte Ag is constitutively presented in both peripheral and mesenteric lymph nodes, leading to abortive activation and deletion of tyrosinase-specific CD8 T cells. Importantly, this Ag is not presented by either radio-sensitive dendritic cells, or by radio-resistant Langerhans cells. Thus, for this endogenous Ag, cross-tolerization does not appear to be an operative mechanism. Instead, we find radioresistant tyrosinase mRNA expression in lymphoid compartments where CD8 T cell deletion occurs. This suggests that direct presentation of tyrosinase by radio-resistant lymph node resident cells is entirely responsible for tolerance to this endogenous melanocyte differentiation Ag.
authors.affiliation: Department of Microbiology and Carter Immunology Center, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Nichols
authors.forename: Yiming
authors.initials: Y
authors.lastname: Chen
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Colella
authors.forename: Clare L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.forename: Victor H
authors.initials: VH
authors.lastname: Engelhard
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology; D008544:Melanocytes / Q000276:immunology*; D008545:Melanoma / Q000276:immunology; D008643:Mesentery / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000276:immunology*; D011828:Radiation Chimera; D011836:Radiation Tolerance; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell; D014442:Monophenol Monooxygenase