title: Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor.
abstract: CD8(+) T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8(+) T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8(+) T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, UAS.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Teague
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.forename: Carla
authors.initials: C
authors.lastname: Fowler
authors.forename: Maria Z
authors.initials: MZ
authors.lastname: Huang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Tan
authors.forename: Junko
authors.initials: J
authors.lastname: Morimoto
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Dossett
authors.forename: Eric S
authors.initials: ES
authors.lastname: Huseby
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlén
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell