title: CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.
abstract: Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This might explain why autoimmunity is often tissue-specific, and it offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens.
authors.affiliation: Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Legoux
authors.affiliation: Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Jong-Baeck
authors.initials: JB
authors.lastname: Lim
authors.affiliation: Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Cauley
authors.affiliation: Howard Hughes Medical Institute, Ludwig Center, and Immunology Program; Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Dikiy
authors.affiliation: Division of Infectious Diseases and Perinatal Institute; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: James
authors.initials: J
authors.lastname: Ertelt
authors.affiliation: Division of Neonatology and Pediatric Molecular and Personalized Medicine Program; University of Rochester, Rochester, NY 14642, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.affiliation: TWINCORE - Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Division of Infectious Diseases and Perinatal Institute; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Sing Sing
authors.initials: SS
authors.lastname: Way
authors.affiliation: Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: jjmoon@mgh.harvard.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001324:Autoantigens; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse