c-Rel: a pioneer in directing regulatory T-cell lineage commitment?

The transcription factor Foxp3 controls the differentiation and function of Treg, but the molecular mechanisms that regulate Foxp3 transcription remain elusive. In particular, signals and factors that open and remodel the Foxp3 locus and imprint developing Treg with a stable Foxp3 phenotype are largely unknown. Two reports in this issue of the European Journal of Immunology, together with recent reports published elsewhere, demonstrate that a member of the NF-kappaB family transcription factors, c-Rel, is required for thymic differentiation of Foxp3(+) Treg. Moreover, c-Rel is shown to regulate Foxp3 transcription directly by binding to cis-regulatory elements at the Foxp3 locus upon TCR/CD28 stimulation, including the promoter and the newly identified conserved non-coding DNA sequence harboring a "permissive" chromatin status in Treg precursors. These findings collectively suggest that c-Rel may act as a pioneer transcription factor in initiating Foxp3 transcription in Treg precursors in the thymus.