Details

Autor(en) / Beteiligte

• 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
• Korn, Thomas

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2019-02, Vol.26 (7), p.1854-1868.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Most Foxp3+ Treg cells in the inflamed CNS express Blimp1•Blimp1 inhibits Dnmt3a and prevents methylation of the Foxp3 locus•IL-6 contributes to methylation of the Foxp3 locus in a Dnmt3a-dependent manner•Blimp1 counteracts the IL-6-driven destabilization of Treg cells An inflammatory environment threatens the stability of Foxp3+ Treg cells. Garg et al. show that by expressing the transcriptional regulator Blimp1, Treg cells resist the IL-6-driven loss of Foxp3 in inflamed tissues. Blimp1 prevents the methylation and reduced expression of Foxp3 through inhibition of the methyltransferase Dnmt3a.