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

Thymically-derived Foxp3(+) regulatory T cells (T-reg) 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-reg contain not only developing but also recirculating cells from the periphery. Although Aire is implicated in the generation of Foxp3(+) T-reg, its role in the biology of recirculating T-reg remains elusive. Here, we show that Aire regulates the suppressive signature of recirculating T-reg independently of the remodeling of the medullary 3D organization throughout life where T-reg reside. Accordingly, the adoptive transfer of peripheral Foxp3(+) T-reg in Aire(KO) recipients led to an impaired suppressive signature upon their entry into the thymus. Furthermore, recirculating T-reg from Aire(KO) 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-reg. Finally, mature mTEC lacking Aire were inefficient in stimulating peripheral T-reg both in polyclonal and antigen-specific co-culture assays. Overall, this study demonstrates that Aire confers to mTEC the ability to restimulate recirculating T-reg, unravelling a novel function for this master regulator in T-reg biology.

Automated summary

This study reveals that Aire regulates the suppressive signature of recirculating T-reg in the thymus. Specifically, Aire controls the suppressive function of recirculating T-reg by regulating the expression of mTEC, which are responsible for restimulating T-reg.