Blimp1 mrevents Methylation of Foxp3 and loss of regulatory T cell identity at sites of inflammation
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
Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2019.01.070
NHMRC Grants
NHMRC/1069075NHMRC/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
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