Origin and T Cell Receptor Diversity of Foxp3⁺CD4⁺CD25⁺ T Cells

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.