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

被引：102

作者：

Garg, Garima ^{[1
]}

Muschaweckh, Andreas ^{[1
]}

Moreno, Helena ^{[2
,3
]}

Vasanthakumar, Ajithkumar ^{[4
,5
]}

Floess, Stefan ^{[6
]}

Lepennetier, Gildas ^{[1
]}

Oellinger, Rupert ^{[7
,8
]}

Zhan, Yifan ^{[4
,5
]}

Regen, Tommy ^{[9
]}

Hiltensperger, Michael ^{[1
]}

Peter, Christian ^{[1
]}

Aly, Lilian ^{[1
,10
]}

Knier, Benjamin ^{[1
]}

Palam, Lakshmi Reddy ^{[11
]}

Kapur, Reuben ^{[11
]}

Kaplan, Mark H. ^{[11
]}

Waisman, Ari ^{[9
]}

Rad, Roland ^{[7
,8
]}

Schotta, Gunnar ^{[2
,3
]}

Huehn, Jochen ^{[6
]}

Kallies, Axel ^{[4
,5
]}

Korn, Thomas ^{[1
,10
]}

机构：

[1] Tech Univ Munich, Dept Expt Neuroimmunol, Klinikum Rechts Isar, Ismaninger Str 22, D-81675 Munich, Germany

[2] Ludwig Maximilians Univ Munchen, Fac Med, Biomed Ctr BMC, Grosshaderner Str 9, D-82152 Planegg Martinsried, Germany

[3] Ludwig Maximilians Univ Munchen, Fac Med, Ctr Integrated Prot Sci Munich, Grosshaderner Str 9, D-82152 Planegg Martinsried, Germany

[4] Univ Melbourne, Peter Doherty Inst Infect & Immun, 792 Elizabeth St, Melbourne, Vic 3000, Australia

[5] Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3052, Australia

[6] Helmholtz Ctr Infect Res, Expt Immunol, Inhoffenstr 7, D-38124 Braunschweig, Germany

[7] Tech Univ Munich, TranslaTUM Canc Ctr, Inst Mol Oncol & Funct Genom, Ismaninger Str 22, D-81675 Munich, Germany

[8] Tech Univ Munich, Dept Med 2, Klinikum Rechts Isar, Ismaninger Str 22, D-81675 Munich, Germany

[9] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Mol Med, Langenbeckstr 1, D-55131 Mainz, Germany

[10] Munich Cluster Syst Neurol SyNergy, Feodor Lynen Str 17, D-81377 Munich, Germany

[11] Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, 1044 West Walnut St, Indianapolis, IN 46202 USA

来源：

CELL REPORTS | 2019年 / 26卷 / 07期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

TRANSCRIPTION FACTORS BLIMP-1; AUTOIMMUNE ENCEPHALOMYELITIS; EPIGENETIC CONTROL; DNA METHYLATION; GENE-REGULATION; HELPER-CELL; EXPRESSION; DIFFERENTIATION; IRF4; GENERATION;

D O I：

10.1016/j.celrep.2019.01.070

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1854 / +

页数：20

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