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.
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The authors declare no competing financial interests.
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We thank D. Gray and R. Boyd for thymic HEL measurement; J. Cyster, E. Unanue and D. Peterson for staining reagents; the staff of Medical Genome Centre for curating the mouse colony; and A. Murtagh, S. Ewing and S. Ward for genotyping. This work was supported by a grant from the Juvenile Diabetes Research Foundation and NHMRC.
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