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

SummaryFoxp3+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.