The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20090300
The Journal of Experimental Medicine, Vol. 206, No. 6, 1245-1252
The Rockefeller University Press, 0022-1007 $30.00
© Guerau-de-Arellano et al.
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BRIEF DEFINITIVE REPORT

 Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity

Mireia Guerau-de-Arellano1,2, Marianne Martinic1,2, Christophe Benoist1,2, and Diane Mathis1,2

1 Section on Immunology and Immunogenetics, Joslin Diabetes Center, and 2 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215

CORRESPONDENCE Diane Mathis OR Christophe Benoist: cbdm{at}hms.harvard.edu

There has long been conceptual and experimental support for, but also challenges to, the notion that the initial period of the immune system's development is particularly important for the establishment of tolerance to self. The display of self-antigens by thymic epithelial cells is key to inducing tolerance in the T lymphocyte compartment, a process enhanced by the Aire transcription factor. Using a doxycycline-regulated transgene to target Aire expression to the thymic epithelium, complementing the Aire knockout in a temporally controlled manner, we find that Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. Surprisingly, Aire could be shut down soon thereafter and remain off for long periods, with few deleterious consequences. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease, which, conversely, could be ameliorated by supplementing neonates with adult lymphocytes. In short, Aire expression during the perinatal period is both necessary and sufficient to induce long-lasting tolerance and avoid autoimmunity. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult, as a previously tolerized T cell pool can buffer newly generated autoreactive T cells that might emerge.

© 2009 Guerau-de-Arellano et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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