Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells

TLDR

Helios, a member of the Ikaros transcription factor family, is preferentially expressed at the mRNA level by regulatory T cells. Helios protein is expressed in all DN2 thymocytes and in 100 % of CD4⁺CD8⁻Foxp3⁺ thymic Tregs, but only in about 70 % of peripheral Foxp3⁺ T cells and is absent from in‑vitro or in‑vivo induced Foxp3⁺ T cells, indicating that Helios marks thymic‑derived Tregs and that a substantial fraction of Foxp3⁺ Tregs arise extrathymically.

Abstract

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 ( approximately 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-beta 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.