Blimp1 mrevents Methylation of Foxp3 and loss of regulatory T cell identity at sites of inflammation
- Author(s)
- Garg, G; Muschaweckh, A; Moreno, H; Vasanthakumar, A; Floess, S; Lepennetier, G; Oellinger, R; Zhan, Y; Regen, T; Hiltensperger, M; Peter, C; Aly, L; Knier, B; Palam, LR; Kapur, R; Kaplan, MH; Waisman, A; Rad, R; Schotta, G; Huehn, J; Kallies, A; Korn, T;
- Details
- Publication Year 2019-02-12,Volume 26,Issue #7,Page 1854-1868 e5
- Journal Title
- Cell Reports
- Publication Type
- Journal Article
- Abstract
- Foxp3(+) 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.
- Publisher
- Cell Press
- Research Division(s)
- Immunology
- PubMed ID
- 30759395
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2019.01.070
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2019.01.070- NHMRC Grants
- NHMRC/1069075, NHMRC/1106378,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-02-11 09:42:31
Last Modified: 2020-02-11 09:44:56