Intraclonal competition limits the fate determination of regulatory T cells in the thymus

Because the deletion of self-reactive T cells is incomplete, thymic development of natural Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) is required for preventing autoimmunity. However, the function of T cell antigen receptor (TCR) specificity in thymic T(reg) cell development remains controversial. To address this issue, we generated a transgenic line expressing a naturally occurring T(reg) cell-derived TCR. Unexpectedly, we found that efficient thymic T(reg) cell development occurred only when the antigen-specific T(reg) cell precursors were present at low clonal frequency (< 1%) in a normal thymus. Using retroviral vectors and bone marrow chimeras, we observed similar activity with two other T(reg) cell-derived TCRs. Our data demonstrate that thymic T(reg) cell development is a 'TCR-instructive' process involving a niche that can be saturable at much lower clonal frequencies than is the niche for positive selection.