Upon antigen recognition within peripheral lymphoid organs, B cells interact with T cells and other immune cells to transiently form morphological structures called germinal centers (GCs), which are required for B cell clonal expansion, immunoglobulin class switching, and affinity maturation. This process, known as the GC response, is an energetically demanding process that requires the metabolic reprogramming of B cells. We showed that the Ras-related guanosine triphosphate hydrolase (GTPase) R-Ras2 (also known as TC21) plays an essential, nonredundant, and B cell–intrinsic role in the GC response. Both the conversion of B cells into GC B cells and their expansion were impaired in mice lacking R-Ras2, but not in those lacking a highly related R-Ras subfamily member or both the classic H-Ras and N-Ras GTPases. In the absence of R-Ras2, activated B cells did not exhibit increased oxidative phosphorylation or aerobic glycolysis. We showed that R-Ras2 was an effector of both the B cell receptor (BCR) and CD40 and that, in its absence, B cells exhibited impaired activation of the PI3K-Akt-mTORC1 pathway, reduced mitochondrial DNA replication, and decreased expression of genes involved in glucose metabolism. Because most human B cell lymphomas originate from GC B cells or B cells that have undergone the GC response, our data suggest that R-Ras2 may also regulate metabolism in B cell malignancies.

在外周淋巴器官内识别抗原后，B 细胞与 T 细胞和其他免疫细胞相互作用，暂时形成称为生发中心 (GC) 的形态结构，这是 B 细胞克隆扩增、免疫球蛋白类别转换和亲和力成熟所必需的。这个过程被称为 GC 反应，是一个能量要求很高的过程，需要 B 细胞的代谢重编程。我们发现与 Ras 相关的三磷酸鸟苷水解酶 (GTPase) R-Ras2（也称为 TC21）在 GC 反应中起着必不可少的、非冗余的和 B 细胞固有的作用。在缺乏 R-Ras2 的小鼠中，B 细胞向 GC B 细胞的转化及其扩增均受损，但在缺乏高度相关的 R-Ras 亚家族成员或经典 H-Ras 和 N-Ras GTPase 的小鼠中则没有。在没有 R-Ras2 的情况下，活化的 B 细胞没有表现出增加的氧化磷酸化或有氧糖酵解。我们发现 R-Ras2 是 B 细胞受体 (BCR) 和 CD40 的效应物，并且在它不存在的情况下，B 细胞表现出 PI3K-Akt-mTORC1 通路的激活受损、线粒体 DNA 复制减少和参与糖代谢的基因。因为大多数人类 B 细胞淋巴瘤起源于 GC B 细胞或经历了 GC 反应的 B 细胞，我们的数据表明 R-Ras2 也可能调节 B 细胞恶性肿瘤的代谢。减少线粒体 DNA 复制，并减少参与葡萄糖代谢的基因的表达。因为大多数人类 B 细胞淋巴瘤起源于 GC B 细胞或经历了 GC 反应的 B 细胞，我们的数据表明 R-Ras2 也可能调节 B 细胞恶性肿瘤的代谢。减少线粒体 DNA 复制，并减少参与葡萄糖代谢的基因的表达。因为大多数人类 B 细胞淋巴瘤起源于 GC B 细胞或经历了 GC 反应的 B 细胞，我们的数据表明 R-Ras2 也可能调节 B 细胞恶性肿瘤的代谢。