Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein
Abstract
Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue– restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed “central” tolerance in controlling autoimmunity.
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We thank G. Losyev, Q.-M. Pham, J. Rasmussen, and R. Saccone for help with flow cytometry, mice, microarray software and chip analysis, respectively, and E. Smith for assistance with the figures. Supported by the W. T. Young Chair fund, NIH grant RO1 DK60027-01 (D.M. and C.B.), Joslin Diabetes Center grant DERC 2 P30 DK36836-16, a Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians and NIH grant KO8-DK59958-01A1 (M.S.A.), an NSF Graduate Research Fellowship and NIH training grant 2T32 DK07260-26 to Joslin Diabetes Center (E.S.V.), Irvington Institute for Immunological Research (L.K.), Juvenile Diabetes Research Foundation (Z.C.), Human Frontier Science Program (S.B.), and an NRSA fellowship in Cancer Immunology (T32CA70083-05) and the Cancer Research Institute (S.J.T.).
Materials and Methods
Figs. S1 to S8
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Science
Volume 298 | Issue 5597
15 November 2002
15 November 2002
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Received: 10 July 2002
Accepted: 19 September 2002
Published in print: 15 November 2002
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