Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells.

Summary Foxp3 + CD4 + CD25 + regulatory T cells can differentiate from Foxp3 − CD4 + medullary thymocytes and Foxp3 − CD4 + naive T cells. However, the impact of these two processes on size and composition of the peripheral repertoire of regulatory T cells is unclear. Here we followed the fate of individual Foxp3 + CD4 + CD25 + thymocytes and T cells in vivo in T cell receptor (TCR) transgenic mice that express a restricted but polyclonal repertoire of TCRs. By utilizing high-throughput single-cell analysis, we showed that Foxp3 + CD4 + peripheral T cells were derived from thymic precursors that expressed a different TCRs than Foxp3 − CD4 + medullary thymocytes and Foxp3 − CD4 + T cells. Furthermore, the diversity of TCRs on Foxp3 + CD4 + regulatory T cells exceeded the diversity of TCRs on Foxp3 − CD4 + naive T cells, even in mice that lack expression of tissue-specific antigens. Our results imply that higher TCR diversity on Foxp3 + regulatory T cells helps these cells to match the specificities of autoreactive and naive T cells.