Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

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Science  01 May 2015:
Vol. 348, Issue 6234, pp. 589-594
DOI: 10.1126/science.aaa7017

Early T cells keep autoimmunity at bay

A major challenge faced by the immune system is to react to foreign substances, such as microbes, while simultaneously tolerating the self. Upsetting this balance leads to autoimmunity. Regulatory T cells (Tregs), are a subset of immune cells that help to maintain this balance. Yang et al. found that murine Treg cells generated very early in life are distinct from those generated in older animals and play an especially important role in keeping autoimmunity in check (see the Perspective by Tanaka and Sakaguchi). These changes are due to differences in the way Tregs develop in the thymus in newborn versus adult mice.

Science, this issue p. 589; see also p. 506


Aire is an important regulator of immunological tolerance, operating in a minute subset of thymic stromal cells to induce transcripts encoding peptides that guide T cell selection. Expression of Aire during a perinatal age window is necessary and sufficient to prevent the multiorgan autoimmunity characteristic of Aire-deficient mice. We report that Aire promotes the perinatal generation of a distinct compartment of Foxp3+CD4+ regulatory T (Treg) cells, which stably persists in adult mice. This population has a role in maintaining self-tolerance, a transcriptome and an activation profile distinguishable from those of Tregs produced in adults. Underlying the distinct Treg populations are age-dependent, Aire-independent differences in the processing and presentation of thymic stromal-cell peptides, resulting in different T cell receptor repertoires. Our findings expand the notion of a developmentally layered immune system.

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