Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3⁺ T regulatory cells

Helios, a member of the Ikaros transcription factor family, is preferentially expressed at the mRNA level by regulatory T cells (Treg cells). We evaluated Helios protein expression using a newly generated mAb and demonstrated that it is expressed in all thymocytes at the double negative 2 stage of thymic development. Although Helios was expressed by 100% of CD4 ⁺CD8^-Foxp3⁺ thymocytes, its expression in peripheral lymphoid tissues was restricted to a subpopulation (∼70%) of Foxp3⁺ T cells in mice and humans. Neither mouse nor human naive T cells induced to express Foxp3 in vitro by TCR stimulation in the presence of TGF-β expressed Helios. Ag-specific Foxp3⁺ T cells induced in vivo by Ag feeding also failed to express Helios. Collectively, these results demonstrate that Helios is potentially a specific marker of thymic-derived Treg cells and raises the possibility that a significant percentage of Foxp3 ⁺ Treg cells are generated extrathymically.