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Science 8 August 2008:
Vol. 321. no. 5890, pp. 843 - 847
DOI: 10.1126/science.1159407
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Reports

Deletional Tolerance Mediated by Extrathymic Aire-Expressing Cells

James M. Gardner,1 Jason J. DeVoss,1 Rachel S. Friedman,2 David J. Wong,3 Ying X. Tan,1 Xuyu Zhou,1 Kellsey P. Johannes,1 Maureen A. Su,1,4 Howard Y. Chang,3 Matthew F. Krummel,2 Mark S. Anderson1*

The prevention of autoimmunity requires the elimination of self-reactive T cells during their development and maturation. The expression of diverse self-antigens by stromal cells in the thymus is essential to this process and depends, in part, on the activity of the autoimmune regulator (Aire) gene. Here we report the identification of extrathymic Aire-expressing cells (eTACs) resident within the secondary lymphoid organs. These stromally derived eTACs express a diverse array of distinct self-antigens and are capable of interacting with and deleting naïve autoreactive T cells. Using two-photon microscopy, we observed stable antigen-specific interactions between eTACs and autoreactive T cells. We propose that such a secondary network of self-antigen–expressing stromal cells may help reinforce immune tolerance by preventing the maturation of autoreactive T cells that escape thymic negative selection.

1 Diabetes Center, University of California San Francisco (UCSF), San Francisco, CA 94122, USA.
2 Department of Pathology, UCSF, San Francisco, CA 94143, USA.
3 Program in Epithelial Biology, Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
4 Department of Pediatrics, UCSF, San Francisco, CA 94122, USA.

* To whom correspondence should be addressed. E-mail: manderson{at}diabetes.ucsf.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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Maintenance of Peripheral Tolerance through Controlled Tissue Homing of Antigen-Specific T Cells in K14-mOVA Mice.
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Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype.
F.-X. Hubert, S. A. Kinkel, P. E. Crewther, P. Z. F. Cannon, K. E. Webster, M. Link, R. Uibo, M. K. O'Bryan, A. Meager, S. P. Forehan, et al. (2009)
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Intestinal Tolerance Is Converted to Autoimmune Enteritis upon PD-1 Ligand Blockade.
E. D. Reynoso, K. G. Elpek, L. Francisco, R. Bronson, A. Bellemare-Pelletier, A. H. Sharpe, G. J. Freeman, and S. J. Turley (2009)
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Science. ISSN 0036-8075 (print), 1095-9203 (online)