Adaptable TCR avidity thresholds for negative selection.
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.
Stojakovic
Milica
M
Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
Salazar-Fontana
Laura I
LI
Tatari-Calderone
Zohreh
Z
Badovinac
Vladimir P
VP
Santori
Fabio R
FR
Kovalovsky
Damian
D
Sant'Angelo
Derek
D
Harty
John T
JT
Vukmanovic
Stanislav
S
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*
D001324:Autoantigens; D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D011948:Receptors, Antigen, T-Cell