e n i c i d e M l a t n e m i r e p x E f o l a n r u o J e h T CORRESPONDENCE Diane Mathis OR Christophe Benoist: cbdm@hms.harvard.edu The Rockefeller University Press $30.00 J. Exp. Med. Vol. 206 No. 6 1245-1252 www.jem.org/cgi/doi/10.1084/jem.20090300 B R I E F D E F I N I T I V E R E P O RT Neonatal tolerance revisited: a per inatal window for Aire control of autoimmunity Mireia Guerau-de-Arellano,1,2 Marianne Martinic,1,2 Christophe Benoist,1,2 and Diane Mathis1,2 1Section on Immunology and Immunogenetics, Joslin Diabetes Center, and 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215 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. Adaptive immune systems face the challenge of discriminating between foreign antigens, against which a response may have to be mounted, and self-constituents, which should be ignored or tolerated. Although there are multiple theoret- ical solutions to the challenge of self/nonself discrimination, Burnet and Fenner (1) proposed as a corollary to the clonal selection theory that the problem can be solved on the basis of time considerations; any antigen to which the im- mune system is exposed in the fetal or early neonatal stages is flagged as self and induces long- term tolerance. Lederberg (2) extended this no- tion by postulating that immature lymphocytes have a heightened sensitivity to tolerance in- duction. This “newborn privilege” was tested by introducing foreign molecules as surrogates for self, and, indeed, it did prove possible to in- duce tolerance by administration of allogeneic cells, viruses, or proteins to neonates but not in adults (3–6). However, neonatal exposure was not always tolerogenic, and the outcome was clearly dose dependent (7, 8). Although related obser- vations already existed in the literature, the strongest challenge to the notion of neonatal tolerance induction came from a trio of studies published in 1996 (9–11), which showed that neonatal lymphocytes could mount full im- mune responses under the appropriate conditions. Ridge et al. (9) pointed out that the differential effects of fetal versus adult exposure to alloge- neic cells highlighted by the Medawar group, long a linchpin of neonatal tolerance, may have been due simply to the large disparities in doses (relative to body size) administered at the two stages. As a result, the notion of neonatal toler- ance was questioned in the field, and more at- tention was given to the influence of concomitant triggering of the innate immune system by in- flammatory and microbial ligands. One issue with experimental testing of neo- natal tolerance induction has been that, going back to the 1950s, investigations mainly relied on the administration of allogeneic or xenogeneic molecules in the tolerization and/or test steps but © 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://creative- commons.org/licenses/by-nc-sa/3.0/). 1245