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Regulatory T (Tregs) cells expressing the transcription factor Foxp3 play an important role in tolerance and prevention of autoimmunity. Thus, there is a need to understand their molecular mechanisms of development and homeostasis, yet the role of antigen recognition by Tregs remains incompletely defined due to the gap in knowledge of natural Treg ligands. Here we identify natural Aire-dependent ligands recognized by endogenous prostate-associated Tregs. We found that recurrent Treg cell clones from independent sequencing studies recognize distinct non-overlapping peptide epitopes derived from the same prostate-specific protein. Here, we investigate the role of cognate antigen expression in the thymus and periphery through the study of T cells reactive to a natural Aire-dependent peptide ligand in wild-type and gene-targeted mice lacking this epitope. Previous evidence suggests that Aire can promote both clonal deletion of antigen-specific T cells and the differentiation of such cells into the Foxp3 regulatory lineage. We demonstrate that antigen expression in the thymus does not impact clonal deletion of polyclonal antigen-specific T cells, but instead is required to direct a substantial number of antigen-specific T cells into the Treg lineage. Further, we show that this skewing to the Treg fate is required to prevent T cell infiltration of the prostate in the absence of inflammation. In all, our data demonstrates that Aire-dependent expression of endogenous self-peptide in the thymus restricts organ-specific autoimmunity by skewing antigen-specific cells to the Treg lineage.


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