PT - JOURNAL ARTICLE AU - Hind Hussein AU - Sébastien Denanglaire AU - Frédéric Van Gool AU - Abdulkader Azouz AU - Yousra Ajouaou AU - Hana El-Khatib AU - Guillaume Oldenhove AU - Oberdan Leo AU - Fabienne Andris TI - Multiple environmental signaling pathways control the differentiation of RORγt-expressing regulatory T cells AID - 10.1101/791244 DP - 2019 Jan 01 TA - bioRxiv PG - 791244 4099 - http://biorxiv.org/content/early/2019/10/02/791244.short 4100 - http://biorxiv.org/content/early/2019/10/02/791244.full AB - 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, save c-Maf, 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+ Treg development strongly relies on signals derived from a complex microbiota, as well as IL-6/STAT3- and TGF-β-derived signals, although deficiency in either signaling pathway barely affects c-Maf expression. Ectopic expression of c-Maf did not rescue RORγt expression in STAT3-deficient Tregs, indicating additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-γ/STAT1 signaling pathway opposes RORγt+ 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+ 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.