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Multiple Environmental Signaling Pathways Control the Differentiation of ROR?t-Expressing Regulatory T Cells.

ABSTRACT: ROR?t-expressing Tregs form a specialized subset of intestinal CD4+ Foxp3+ 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 ROR?t expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of ROR?t+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that ROR?t+ 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-?-derived signals act in favor of ROR?t+ Treg development. Ectopic expression of c-Maf did not rescue ROR?t expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-?/STAT1 signaling pathway acts as a negative regulator of ROR?t+ Treg differentiation in a c-Maf independent fashion. These data thus argue for a complex integrative signaling network that finely tunes ROR?t expression in Tregs. The finding that type 1 inflammation impedes ROR?t+ 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.

SUBMITTER: Hussein H

PROVIDER: S-EPMC6961548 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells.

Hussein Hind H Denanglaire Sébastien S Van Gool Frédéric F Azouz Abdulkader A Ajouaou Yousra Y El-Khatib Hana H Oldenhove Guillaume G Leo Oberdan O Andris Fabienne F

Frontiers in immunology 20200108

RORγt-expressing Tregs form a specialized subset of intestinal CD4+ Foxp3+ 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+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that RORγt<sup ...[more]

PMID: 31998303

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Project description:AimsRetinoic acid receptor-related orphan nuclear receptor ?t (ROR?t) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that ROR?t plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of ROR?t in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.Methods and resultsMI was generated by ligating coronary artery. The expression of ROR?t and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that ROR?t-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that ROR?t-expressing cells were released from the spleen at day 1 after MI. Though ROR?t-expressing cells in spleen expressed ??TCR or CD4, ??TCR+ cells were major population of ROR?t-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of ROR?t-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at ROR?t locus (ROR?t+/- mice), which physiologically showed reduced expression of ROR?t mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in ROR?t+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in ROR?t+/- mice 7 days after MI (Injured area: ROR?t+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: ROR?t+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: ROR?t+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in ROR?t+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of ROR?t, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in ROR?t+/- hearts.ConclusionsHeterozygous deletion of ROR?t gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that ROR?t-expressing cells contribute to tissue repair in infarcted myocardium.

Dataset Information

Multiple Environmental Signaling Pathways Control the Differentiation of ROR?t-Expressing Regulatory T Cells.

Publications

Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells.

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