title: Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state.
abstract: Tolerant self-antigen-specific CD8 T cells fail to proliferate in response to antigen, thereby preventing autoimmune disease. By using an in vivo mouse model, we show that tolerant T cells proliferate and become functional under lymphopenic conditions, even in a tolerogenic environment. However, T cell rescue is only transient, with tolerance reimposed upon lymphorepletion even in the absence of tolerogen (self-antigen), challenging the prevailing paradigm that continuous antigen exposure is critical to maintain tolerance. Genome-wide messenger RNA and microRNA profiling revealed that tolerant T cells have a tolerance-specific gene profile that can be temporarily overridden under lymphopenic conditions but is inevitably reimposed, which suggests epigenetic regulation. These insights into the regulatory mechanisms that maintain or break self-tolerance may lead to new strategies for the treatment of cancer and autoimmunity.
authors.affiliation: Department of Immunology, University of Washington (UW), Seattle, WA 98195, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schietinger
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Basom
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Blattman
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology / Q000637:transplantation; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006706:Homeostasis; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017634:Self Tolerance / Q000235:genetics; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D001324:Autoantigens; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse