Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Austria.
Institute for Biomedical Aging Research, University of Innsbruck, Austria.
FEBS J. 2019 Sep;286(18):3566-3581. doi: 10.1111/febs.14934. Epub 2019 Jun 3.
Upon activation by antigen, B cells form germinal centres where they clonally expand and introduce affinity-enhancing mutations into their B-cell receptor genes. Somatic mutagenesis and class switch recombination (CSR) in germinal centre B cells are initiated by the activation-induced cytidine deaminase (AID). Upon germinal centre exit, B cells differentiate into antibody-secreting plasma cells. Germinal centre maintenance and terminal fate choice require transcriptional reprogramming that associates with a substantial reconfiguration of DNA methylation patterns. Here we examine the role of ten-eleven-translocation (TET) proteins, enzymes that facilitate DNA demethylation and promote a permissive chromatin state by oxidizing 5-methylcytosine, in antibody-mediated immunity. Using a conditional gene ablation strategy, we show that TET2 and TET3 guide the transition of germinal centre B cells to antibody-secreting plasma cells. Optimal AID expression requires TET function, and TET2 and TET3 double-deficient germinal centre B cells show defects in CSR. However, TET2/TET3 double-deficiency does not prevent the generation and selection of high-affinity germinal centre B cells. Rather, combined TET2 and TET3 loss-of-function in germinal centre B cells favours C-to-T and G-to-A transition mutagenesis, a finding that may be of significance for understanding the aetiology of B-cell lymphomas evolving in conditions of reduced TET function.
当被抗原激活时，B 细胞形成生发中心，在那里它们进行克隆扩增，并在其 B 细胞受体基因中引入亲和力增强突变。生发中心 B 细胞中的体细胞突变和类别转换重组（CSR）是由激活诱导的胞嘧啶脱氨酶（AID）引发的。生发中心退出后，B 细胞分化为分泌抗体的浆细胞。生发中心的维持和终末命运选择需要转录重编程，这与 DNA 甲基化模式的大量重新配置相关。在这里，我们研究了 ten-eleven-translocation（TET）蛋白在抗体介导的免疫中的作用，这些蛋白是通过氧化 5-甲基胞嘧啶来促进 DNA 去甲基化和促进允许性染色质状态的酶。使用条件性基因敲除策略，我们表明 TET2 和 TET3 指导生发中心 B 细胞向分泌抗体的浆细胞的过渡。最佳的 AID 表达需要 TET 功能，并且 TET2 和 TET3 双缺陷生发中心 B 细胞显示 CSR 缺陷。然而，TET2/TET3 双缺陷并不阻止高亲和力生发中心 B 细胞的产生和选择。相反，生发中心 B 细胞中 TET2 和 TET3 的联合功能丧失有利于 C 到 T 和 G 到 A 的转换突变，这一发现可能对理解在 TET 功能降低的情况下发生的 B 细胞淋巴瘤的发病机制具有重要意义。
