Aire regulates negative selection of organ-specific T cells.
Autoimmune polyendocrinopathy syndrome type 1 is a recessive Mendelian disorder resulting from mutations in a novel gene, AIRE, and is characterized by a spectrum of organ-specific autoimmune diseases. It is not known what tolerance mechanisms are defective as a result of AIRE mutation. By tracing the fate of autoreactive CD4+ T cells with high affinity for a pancreatic antigen in transgenic mice with an Aire mutation, we show here that Aire deficiency causes almost complete failure to delete the organ-specific cells in the thymus. These results indicate that autoimmune polyendocrinopathy syndrome 1 is caused by failure of a specialized mechanism for deleting forbidden T cell clones, establishing a central role for this tolerance mechanism.
Liston
Adrian
A
ACRF Genetics Lab, Medical Genome Centre, John Curtin School of Medical Research, The Australian National University, ACT 2601 Australia.
Lesage
Sylvie
S
Wilson
Judith
J
Peltonen
Leena
L
Goodnow
Christopher C
CC
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017637:Clonal Deletion / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000276:immunology; D010179:Pancreas / Q000276:immunology; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
D001324:Autoantigens; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D000096927:AIRE Protein