Journal
CELL REPORTS
Volume 26, Issue 7, Pages 1854-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.01.070
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Funding
- Deutsche Forschungsgemeinschaft [SFB1054-B06, TRR128, SFB738-C07, SFB1243-A03, SFB1321, 329628492]
- German Ministry of Education and Research (BMBF)
- Helmholtz Gemeinschaft [ZT-0027]
- ERC [CoG 647215]
- National Health and Medical Research Council [1069075, 1106378]
- Sylvia and Charles Viertel foundation
- National Multiple Sclerosis Society [NMSS RG 1707-28780]
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC Independent Research Institute Infrastructure Support scheme
- National Health and Medical Research Council of Australia [1106378, 1069075] Funding Source: NHMRC
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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.
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