Abstract
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.
Highlights
Foxp3+CD4+ regulatory T cells (Tregs) play a crucial role in the maintenance of immune homeostasis and prevention of excessive immune responses [1,2,3]
The instable Foxp3 expression by in vitro generated induced Foxp3+ Tregs (iTregs) is associated with decreased demethylation of the Tregspecific demethylated region (TSDR) at the Foxp3 locus, which is highly demethylated within thymus-derived Tregs (tTregs) and peripherallyinduced Tregs (pTregs) subsets [6,7,8]
Kinetic studies demonstrated that three injections of the IL-2/JES6-1 complex resulted in a brief expansion of Tregs which peaked on day 5 and gradually declined on days 8 and 15
Summary
Foxp3+CD4+ regulatory T cells (Tregs) play a crucial role in the maintenance of immune homeostasis and prevention of excessive immune responses [1,2,3]. Mice with a deletion in TGF-β1 or animals lacking Smad and Smad in T cells have been show to exhibit normal development of tTregs but have significantly decreased numbers of pTregs [9, 10], suggesting that TGF-β signalling pathway is essential for the maintenance of Foxp expression and function of Tregs in peripheral organs. Mice lacking proteins involved in NF-κB activation such as PKCΘ, Bcl, CARMA1 and MALT1 display impaired Treg cell development [14, 21] These data revealed that NF-κB, originally described as a pro-inflammatory factor, is one of key regulators of development of tTregs with anti-inflammatory properties. C-Rel deficient mice still exhibit moderate Foxp3+ Treg cell frequencies in the peripheral organs prompting us to investigate the origin of these cells
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