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Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells.
- Source :
-
Frontiers in immunology [Front Immunol] 2020 Jan 08; Vol. 10, pp. 3007. Date of Electronic Publication: 2020 Jan 08 (Print Publication: 2019). - Publication Year :
- 2020
-
Abstract
- RORγt-expressing Tregs form a specialized subset of intestinal CD4 <superscript>+</superscript> Foxp3 <superscript>+</superscript> cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of RORγt expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of RORγt <superscript>+</superscript> Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that RORγt <superscript>+</superscript> Treg development is controled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3- and TGF-β-derived signals act in favor of RORγt <superscript>+</superscript> Treg development. Ectopic expression of c-Maf did not rescue RORγt expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-γ/STAT1 signaling pathway acts as a negative regulator of RORγt <superscript>+</superscript> Treg differentiation in a c-Maf independent fashion. These data thus argue for a complex integrative signaling network that finely tunes RORγt expression in Tregs. The finding that type 1 inflammation impedes RORγt <superscript>+</superscript> Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.<br /> (Copyright © 2020 Hussein, Denanglaire, Van Gool, Azouz, Ajouaou, El-Khatib, Oldenhove, Leo and Andris.)
- Subjects :
- Animals
Immunophenotyping
Mice
Mice, Transgenic
Proto-Oncogene Proteins c-maf genetics
Proto-Oncogene Proteins c-maf metabolism
STAT3 Transcription Factor metabolism
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
T-Lymphocytes, Regulatory cytology
Transforming Growth Factor beta metabolism
Cell Differentiation genetics
Cell Differentiation immunology
Gene Expression
Nuclear Receptor Subfamily 1, Group F, Member 3 genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism
Signal Transduction
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 31998303
- Full Text :
- https://doi.org/10.3389/fimmu.2019.03007