title: Adaptable TCR avidity thresholds for negative selection.
abstract: Central tolerance plays a significant role in preventing autoimmune diseases by eliminating T cells with high and intermediate avidity for self. To determine the manner of setting the threshold for deletion, we created a unique transgenic mouse strain with a diverse T cell population and globally increased TCR avidity for self-peptide/MHC complexes. Despite the adaptations aimed at reducing T cell reactivity (reduced TCR levels and increased levels of TCR signaling inhibitor CD5), transgenic mice displayed more severe experimental allergic encephalomyelitis and lupus. The numbers and activity of natural (CD4(+)CD25(+)) regulatory T cells were not altered. These findings demonstrate that the threshold for deletion is adaptable, allowing survival of T cells with higher avidity when TCR avidity is globally increased.
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Milica
authors.initials: M
authors.lastname: Stojakovic
authors.forename: Laura I
authors.initials: LI
authors.lastname: Salazar-Fontana
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Tatari-Calderone
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Santori
authors.forename: Damian
authors.initials: D
authors.lastname: Kovalovsky
authors.forename: Derek
authors.initials: D
authors.lastname: Sant'Angelo
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
authors.forename: Stanislav
authors.initials: S
authors.lastname: Vukmanovic
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity; D018956:CD5 Antigens / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D011948:Receptors, Antigen, T-Cell