Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage

• Aire impacts the peripheral repertoire of both Treg cells and Tconv cells
• The autoimmune defect in Aire−/− mice maps to the Tconv cell compartment
• Treg-biased clones are diverted into the Tconv cell subset in Aire−/− mice
• Diverted clones dominate the Tconv cell infiltrate in prostatic lesions

SummaryThe promiscuous expression of tissue-restricted antigens in the thymus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3+ regulatory T (Treg) cells, suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. Here, examination of autoimmune lesions in Aire−/− mice revealed an unexpected third possibility. We found that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that were preferentially expressed by Foxp3+ Treg cells in Aire+/+ mice. Thus, Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage; dysregulation of this process results in the diversion of Treg cell-biased clonotypes into pathogenic conventional T cells.

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