Transcription factor c-Rel is indispensable for generation of thymic but not of peripheral Foxp3⁺ regulatory T cells

The transcription factor c-Rel has been shown to be crucial for development of regulatory T cells (Tregs). Recent studies have reported that the expression of transcription factor Helios in Foxp3⁺ Tregs correlates with thymic origin of these cells (tTregs). Notably, we found that only the Helios⁺Foxp3⁺ Treg cell population was substantially reduced in c-Rel deficient mice. In contrast to a defective tTreg development, we observed an expansion of mucosal Tregs during the induction of acute colitis in rel^-/- mice. Furthermore, we found a preferential accumulation of Helios^-Foxp3⁺ Tregs in aged c-Rel deficient mice. This unexpected finding, together with the observation that naïve CD4⁺ T cells convert into Tregs in vitro in the absence of c-Rel and presence of IL-2, provide an evidence that extra-thymic generation of induced and peripheral Tregs (iTregs and pTregs) is independent of c-Rel. Moreover, the treatment with IL-2/anti-IL-2 mAb (JES6-1) resulted in a widespread increase of Helios⁺Foxp3⁺ Tregs in both wild-type (WT) and rel^-/- mice. These data suggest that exogenous IL-2 administration compensates for defective IL-2 production and reduced tTreg numbers in c-Rel deficient mice. Our findings reveal that c-Rel is essential for the generation of tTregs but not for that of pTregs and iTregs.