Autoimmune Regulator (Aire) is critical for the thymic development of naturally occurring Treg specificities (P1185)

Abstract

Abstract While the transcription factor Autoimmune Regulator (AIRE) has been shown to play a critical role in establishing immune tolerance through the negative selection of T cells reactive to peripheral antigens, the role of AIRE in the thymic development of Foxp3+ regulatory T cells (Tregs) remains controversial. Previously in our lab, the naturally occurring Treg T-cell receptor (TCR) “MJ23”, isolated from the prostates of tumor-bearing TRAMP mice, was used to create a monospecific TCR transgenic (tg) mouse model. By generating MJ23 tg low frequency bone marrow chimeras (BMCs), we determined that the MJ23 TCR facilitates thymic Treg development in both male and female hosts, even though MJ23 T cells are reactive to a prostate-specific antigen. By generating MJ23 BMCs into Aire+/+ and Aire-/- hosts, we determined that the thymic development of MJ23 Tregs was Aire-dependent, regardless of host gender. These results were also observed for a second naturally occurring Treg specificity. In BMCs, we found no evidence of Aire-dependent MJ23 negative selection, suggesting that for this specificity, Aire plays an exclusive role in the thymic selection of Tregs. Finally, while autoimmune prostatitis was observed in male Aire-/- mice, we found no indications of Foxp3neg MJ23 T cell expansion in Aire-/- BMC hosts. In sum, our data provide mechanistic evidence that a subset of peripheral organ-specific Tregs are dependent on Aire for their selection into the Foxp3+ Treg lineage in the thymus.