title: Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance.
abstract: Autoimmune diseases tend to be chronic and progressive, but how these responses are sustained is not clear. One cell type that might contribute to autoimmunity is the cytotoxic T lymphocyte (CTL), which, as a consequence of causing tissue destruction and production of cytokines, could provide a sustained supply of antigen and inflammatory signals for dendritic cells to maintain immune stimulation. Here we examined whether such CTL-mediated tissue damage alone could provide antigen in the right context to recruit immune effectors and sustain autoimmunity. We show that while CTL-mediated tissue damage caused the release of self-antigens that stimulated the proliferation of naive autoreactive CD8(+) T cells, such responses failed to precipitate disease and, instead, led to deletional tolerance. These findings indicate that despite the capacity of CTLs to produce inflammatory cytokines and to cause tissue damage, their responses are not sustaining, but instead favor induction of self-tolerance.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Parish
authors.forename: Jason
authors.initials: J
authors.lastname: Waithman
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Davey
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.forename: Justine D
authors.initials: JD
authors.lastname: Mintern
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Sutherland
authors.forename: Francis R
authors.initials: FR
authors.lastname: Carbone
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000382:microbiology*
chemical_list: D000941:Antigens; D010047:Ovalbumin