c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis

Foxp3+ regulatory T (Treg) cells are essential for immunological tolerance and homeostasis. In peripheral tissues, Treg cells acquire enhanced suppressive functions and co-opt distinct transcriptional modules, allowing context and tissue-dependent immune regulation. Here we show that the transcription factor c-Maf was highly expressed by effector Treg cells and controlled their IL-10 production. In the intestine, c-Maf was required for the differentiation of RORgt+ microbiota-dependent Treg cells, and restricted their production of inflammatory cytokines. Consequently, Treg cell-specific loss of c-Maf resulted in perturbed intestinal homeostasis, microbial dysbiosis and a selective failure to control Th17 responses during homeostasis and upon chemically induced epithelial damage. Molecular profiling revealed that c-Maf regulated expression of key genes of the transcriptional signature of intestinal Treg cells, including Rorc and Il10. Thus, our study identifies a key role of c-Maf in preserving the identity and function of intestinal Treg cells, essential for the control of intestinal immune homeostasis. Overall design: Transcriptional profiling of control (Foxp3Cre-YFP, "WT") and Maf-KO (Maffl/fl x Foxp3Cre-YFP, "KO") Treg cells sorted from Gut and Spleen

Foxp3阳性调节性T（Treg）细胞是免疫耐受与免疫稳态维持的核心细胞群。在外周组织中，Treg细胞可获得增强的抑制功能，并调控独特的转录模块，从而实现情境特异性与组织依赖性的免疫调控。本研究发现，转录因子c-Maf在效应性Treg细胞中高表达，并可调控其IL-10的产生。在肠道中，c-Maf是RORγt阳性菌群依赖性Treg细胞分化所必需的，并可抑制其炎性细胞因子的分泌。因此，Treg细胞特异性缺失c-Maf会导致肠道稳态紊乱、菌群失调，并在基础稳态及化学诱导的上皮损伤过程中，无法选择性调控Th17细胞应答。转录组分析显示，c-Maf可调控肠道Treg细胞转录特征的关键基因表达，包括Rorc与Il10。综上，本研究阐明了c-Maf在维持肠道Treg细胞特性与功能中的关键作用，而这对于调控肠道免疫稳态至关重要。实验设计：对从肠道与脾脏分选得到的对照组（Foxp3Cre-YFP, "WT"）与Maf敲除组（Maffl/fl × Foxp3Cre-YFP, "KO"）的Treg细胞开展转录组分析。