Nonself-Antigens Are the Cognate Specificities of Foxp3⁺ Regulatory T Cells

The majority of regulatory Foxp3⁺CD4⁺ T cells naturally arises in the thymus. It has been proposed that T cell receptors (TCRs) on these cells recognize self-MHC class II-peptide complexes with high or higher affinity and that their specificities mirror specificities of autoreactive T cells. Here, we analyzed hundreds of TCRs derived from regulatory or nonregulatory T cells and found little evidence that the former population preferably recognizes self-antigens as agonists. Instead, these cells recognized foreign MHC-peptide complexes as often as nonregulatory T cells. Our results show that high-affinity, autoreactive TCRs are rare on all CD4⁺ T cells and suggest that selecting self-peptide is different from the peptide that activates the same regulatory T cells in the periphery.