IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Tr1 deficient in TFs RNA-seq]

IL-27 is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, Atf3) and 2 negative (Irf9, Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators Prdm1 and Maf that cooperatively drive the expression of signature genes induced by IL-27 in Type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3+regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying the ll10 deficient mice. Our work provides insights for IL-27 driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets. Bulk RNA-seq for in vitro derived Tr1 cells deficient in various transcription factors

白细胞介素27（IL-27）是一类免疫调节性细胞因子，可通过包括诱导白细胞介素10（IL-10）在内的多种机制抑制炎症反应，但其介导自身多样生物学功能的转录调控网络仍未明确。本研究将时序RNA谱分析（temporal RNA profiling）与计算算法相结合，在T细胞中预测得到79个受IL-27诱导的转录因子。我们验证了11种已知的IL-10调控因子，并新发现5种阳性调控因子（Cebpb、Fosl2、Tbx21、Hlx、Atf3）与2种阴性调控因子（Irf9、Irf8），由此构建了经实验优化的IL-10调控网络。本研究报道了两个核心调控因子Prdm1与Maf：二者可协同驱动1型调节性T细胞（Type 1 regulatory T cells）中IL-27诱导的特征基因表达，介导所有辅助性T细胞（T helper cells）亚群的IL-10表达，并决定结肠Foxp3阳性调节性T细胞（Foxp3+ regulatory T cells）的调节表型。Prdm1/Maf双基因敲除小鼠可发生自发性结肠炎，其表型与IL-10缺陷小鼠一致。本研究为解析IL-27介导的转录调控网络提供了新的见解，并鉴定出两个共享的IL-10调控因子，它们可跨辅助性T细胞亚群协调免疫调节程序。本数据集包含体外诱导的各类转录因子缺陷型1型调节性T细胞的批量RNA测序（Bulk RNA-seq）数据。