Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide

Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR) to undergo selection to become CD4(+)CD25(+) regulatory T cells. Selection of CD4(+)CD25(+) thymocytes appears to require a TCR with high affinity for a self peptide because thymocytes that bear TCRs with low affinity do not undergo selection into this pathway. Our findings indicate that specificity for self-peptides directs the selection of CD4(+)CD25(+) regulatory thymocytes by a process that is distinct from positive selection and deletion.