Differential expression of Helios in regulatory T cells

CD4+CD25+ T cells (Tregs) represent the dominant arm of immune regulation during an immune response. Dedicated FoxP3 + Tregs are generated in the thymus (nTregs) as well as induced in the periphery (iTregs). However, our understanding of conditions that promote the induction or expansion of these cells remains incomplete. In addition, deciphering molecular mechanisms that promote the stable expression of FoxP3+ has been challenging and confusing at best. In this body of work, we have used an autochthonous cancer model to evaluate the transcriptional profile of tumor-specific CD4 T cells encountering cognate antigen in vivo. Not surprisingly, tumor recognition led to the development of regulatory T cells as measured by upregulation of FoxP3 and in vitro suppressive ability. Interestingly, we found that Helios, a T cell restricted Ikaros transcription factor family member, was also upregulated in these cells. However, unlike FoxP3 expression, Helios up-regulation was absent in in vitro induced regulatory T cells and its ectopic expression induced apoptosis. On a functional level, suppression of Helios in CD4+CD25+ T cells by siRNA oligonucletides markedly abrogated the suppressive function of Human Tregs. Additionally, Helios expression was required for the maintenance of FoxP3 mRNA levels. Finally, we demonstrated that Helios specifically binds to the FoxP3 promoter region in EL4 cells. Taken together, these data suggest that tumors not only induce regulatory T cells but also support the expansion of thymic Tregs. Moreover, in light of other published work, these data suggest that Helios expression plays an important yet redundant role in maintaining a stable expression of FoxP3 in nTregs.