Garg, GarimaMuschaweckh, AndreasMoreno, HelenaVasanthakumar, AjithkumarFloess, StefanLepennetier, GildasOellinger, RupertZhan, YifanRegen, TommyHiltensperger, MichaelPeter, ChristianAly, LilianKnier, BenjaminPalam, Lakshmi ReddyKapur, ReubenKaplan, Mark H.Waisman, AriRad, RolandSchotta, GunnarHuehn, JochenKallies, AxelKorn, Thomas2019-07-302019-07-302019-02-12Garg, G., Muschaweckh, A., Moreno, H., Vasanthakumar, A., Floess, S., Lepennetier, G., … Korn, T. (2019). Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation. Cell reports, 26(7), 1854–1868.e5. doi:10.1016/j.celrep.2019.01.070https://hdl.handle.net/1805/20025Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesBlimp1CNSCNS2DNA methyltransferasesFoxp3Interleukin-6Epigenetic regulationInflammationRegulatory T cellsArticle