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Aire regulates negative selection of organ-specific T cells

Nature Immunology volume 4, pages 350–354 (2003)Cite this article

Abstract

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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Figure 1: Failure to delete pancreatic islet reactive T cells in thymus of Aire−/− mice.
Figure 2: Failure of thymic deletion in Aire−/− mice.
Figure 3: Islet-specific T cells in the peripheral repertoire of Aire−/− mice.

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Acknowledgements

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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Authors and Affiliations

  1. ACRF Genetics Lab, Medical Genome Centre, John Curtin School of Medical Research, The Australian National University, ACT, 2601, Australia

    Adrian Liston, Sylvie Lesage, Judith Wilson & Christopher C. Goodnow

  2. Department of Medical Genetics and Molecular Medicine, University of Helsinki and National Public Health Institute, Finland

    Leena Peltonen

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Correspondence to Christopher C. Goodnow.

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Liston, A., Lesage, S., Wilson, J. et al. Aire regulates negative selection of organ-specific T cells. Nat Immunol 4, 350–354 (2003). https://doi.org/10.1038/ni906

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