Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation

Garg, Garima; Muschaweckh, Andreas; Moreno, Helena; Vasanthakumar, Ajithkumar; Floess, Stefan; Lepennetier, Gildas; Oellinger, Rupert; Zhan, Yifan; Regen, Tommy; Hiltensperger, Michael; Peter, Christian; Aly, Lilian; Knier, Benjamin; Palam, Lakshmi Reddy; Kapur, Reuben; Kaplan, Mark H.; Waisman, Ari; Rad, Roland; Schotta, Gunnar; Huehn, Jochen; Kallies, Axel und Korn, Thomas (2019): Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation. In: Cell Reports, Bd. 26, Nr. 7

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, weestablish 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 isdependentonthe 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2211-1247
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198