Department of Medical Area, University of Udine, Udine, Italy.
German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
Eur J Immunol. 2019 Aug;49(8):1213-1225. doi: 10.1002/eji.201848025. Epub 2019 May 7.
Among the family of regulatory B cells, the subset able to produce interleukin-10 (IL-10) is the most studied, yet its biology is still a matter of investigation. The DNA methylation profiling of the il-10 gene locus revealed a novel epigenetic signature characterizing murine B cells ready to respond through IL-10 synthesis: a demethylated region located 4.5 kb from the transcription starting site (TSS), that we named early IL10 regulatory region (eIL10rr). This feature allows to distinguish B cells that are immediately prone and developmentally committed to IL-10 production from those that require a persistent stimulation to exert an IL-10-mediated regulatory function. These late IL-10 producers are instead characterized by a delayed IL10 regulatory region (dIL10rr), a partially demethylated DNA portion located 9 kb upstream from the TSS. A demethylated region was also found in human IL-10-producing B cells and, very interestingly, in some B-cell malignancies, such as chronic lymphocytic leukemia and mantle cell lymphoma, characterized by an immunosuppressive microenvironment. Our findings define murine and human regulatory B cells as an epigenetically controlled functional state of mature B cell subsets and open a new perspective on IL-10 regulation in B cells in homeostasis and disease.
在调节性 B 细胞家族中，能够产生白细胞介素 10（IL-10）的亚群是研究最多的，但它的生物学仍然是一个研究的课题。il-10 基因座的 DNA 甲基化分析揭示了一种新的表观遗传特征，该特征可用于表征准备通过 IL-10 合成做出反应的小鼠 B 细胞：位于转录起始位点（TSS）4.5 kb 处的去甲基化区域，我们将其命名为早期 IL10 调节区（eIL10rr）。这一特征可以区分那些立即易于产生和发育上承诺产生 IL-10 的 B 细胞，以及那些需要持续刺激才能发挥 IL-10 介导的调节功能的 B 细胞。这些晚期 IL-10 产生者的特征是延迟的 IL10 调节区（dIL10rr），这是 TSS 上游 9 kb 处部分去甲基化的 DNA 部分。在人类产生白细胞介素 10 的 B 细胞中也发现了一个去甲基化区域，而且非常有趣的是，在一些 B 细胞恶性肿瘤中，如慢性淋巴细胞白血病和套细胞淋巴瘤，其特征是免疫抑制性微环境。我们的发现将鼠类和人类调节性 B 细胞定义为成熟 B 细胞亚群的受表观遗传控制的功能状态，并为 B 细胞在稳态和疾病中的 IL-10 调节开辟了新的视角。
