Germinal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione. MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway. Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination.

生发中心 (GC) B 细胞对于 GC 的生成和长效体液免疫至关重要。在这里，我们报道一碳代谢决定 GC B 细胞的形成和反应。在 CD40 刺激下，GC B 细胞选择性上调亚甲基四氢叶酸脱氢酶 2 (MTHFD2) 表达，以产生嘌呤和抗氧化剂谷胱甘肽。 MTHFD2 耗竭会降低 GC B 细胞频率和抗原特异性抗体的产生。此外，补充核苷酸和抗氧化剂足以通过激活雷帕霉素复合物 1 信号通路的哺乳动物靶点来促进 GC B 细胞在体外和体内的形成和功能。此外，我们发现抗原刺激增强了YY1与Mthfd2启动子的结合并促进MTHFD2转录。有趣的是，这些发现可以推广到磷酸戊糖途径，这是还原能力和核苷酸的另一个主要来源。因此，这些结果表明，GC B 细胞的形成和反应需要增加核苷酸合成和氧化还原平衡的能力，揭示了 GC B 细胞命运决定的一个关键方面。