Recirculating Foxp3 regulatory T cells are restimulated in the thymus under Aire control.

Thymically-derived Foxp3 regulatory T cells (T) critically control immunological tolerance. These cells are generated in the medulla through high affinity interactions with medullary thymic epithelial cells (mTEC) expressing the Autoimmune regulator (Aire). Recent advances have revealed that thymic T contain not only developing but also recirculating cells from the periphery. Although Aire is implicated in the generation of Foxp3 T, its role in the biology of recirculating T remains elusive. Here, we show that Aire regulates the suppressive signature of recirculating T independently of the remodeling of the medullary 3D organization throughout life where T reside. Accordingly, the adoptive transfer of peripheral Foxp3 T in Aire recipients led to an impaired suppressive signature upon their entry into the thymus. Furthermore, recirculating T from Aire mice failed to attenuate the severity of multiorgan autoimmunity, demonstrating that their suppressive function is altered. Using bone marrow chimeras, we reveal that mTEC-specific expression of Aire controls the suppressive signature of recirculating T. Finally, mature mTEC lacking Aire were inefficient in stimulating peripheral T both in polyclonal and antigen-specific co-culture assays. Overall, this study demonstrates that Aire confers to mTEC the ability to restimulate recirculating T, unravelling a novel function for this master regulator in T biology.