RNASeq: Aryl hydrocarbon receptor governs a transcriptional programme that determines regulatory B cell differentiation and function

Regulatory B cells (Breg) play a critical role in the control of autoimmunity and inflammation. Although IL-10 is considered the hallmark for the identification of Bregs, the molecular programme that controls IL-10 production in Bregs is yet to be defined. Here, we demonstrate that aryl hydrocarbon receptor (AhR) controls the differentiation and function of IL-10-producing Bregs. Deficiency of AhR-expressing B cells drastically reduces IL-10 production by B cells. This leads to the unrestrained differentiation of T helper (Th)17 cells and a significant reduction in the percentage of regulatory T cells (Treg), which increases the severity of experimental arthritis when compared to control animals with AhR-sufficient B cells. A combination of chromatin-landscape profiling by ATAC-seq and transcriptome analyses by RNA-seq demonstrated that a loss of AhR expression in B cells not only reduces IL-10 expression by Bregs, defined as CD21hiCD24hi B cells, but also promotes a pro-inflammatory programme in CD21hiCD24hi B cells, even under Breg inducing conditions. Thus, AhR acts as a master transcriptional regulator of Breg differentiation by implementing a molecular programme that controls IL-10 production and represses pro-inflammatory cytokine production.调节性B细胞（Regulatory B cells, Breg）在自身免疫与炎症的调控中发挥关键作用。尽管白细胞介素10（IL-10）被视为鉴定Breg的标志性标志物，但调控Breg产生IL-10的分子程序仍有待阐明。本研究证实，芳香烃受体（aryl hydrocarbon receptor, AhR）可调控产IL-10的Breg的分化与功能。缺失表达AhR的B细胞会大幅降低B细胞的IL-10产生水平，这会导致辅助性T细胞17（T helper 17, Th17）的分化不受限制，同时显著降低调节性T细胞（Treg）的占比；相较于AhR表达充足的B细胞对照组动物，该变化会加重实验性关节炎的严重程度。通过转座酶可及性染色质测序（ATAC-seq）开展染色质景观分析、结合RNA测序（RNA-seq）进行转录组分析的结果显示，B细胞中AhR表达缺失，不仅会降低被定义为CD21hiCD24hi B细胞的Breg的IL-10表达水平，还会在CD21hiCD24hi B细胞中激活促炎程序，即便在Breg诱导条件下亦是如此。综上，AhR通过执行调控IL-10产生并抑制促炎细胞因子生成的分子程序，成为Breg分化的核心转录调控因子。