Intraclonal competition limits regulatory T cell fate determination in the thymus

Because the deletion of self-reactive T cells is incomplete, thymic development of natural Foxp3(+)CD4(+) regulatory T (T(reg)) cells is required for preventing autoimmunity. However, the role of T cell 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. Surprisingly, efficient thymic T(reg) cell development occurred only when the antigen-specific T(reg) cell precursors were present at low clonal frequency (<1%) within a normal thymus. Using retroviral vectors and bone marrow chimeras, we observed similar behavior with two other T(reg) cell-derived TCRs. These data demonstrate that thymic T(reg) cell development is a TCR-instructive process involving a niche which can be saturable at much lower clonal frequencies than the niche for positive selection.