Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1^f/fMb1^Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

单羧酸转运蛋白 1 （MCT1） 在细胞代谢和能量供应中发挥重要作用。尽管 MCT1 在活化的 B 细胞中高度表达，但尚不清楚 MCT1 控制的单羧酸盐转运如何在功能上与葡萄糖代谢过程中的抗体产生耦合。在这里，我们报道了 MCT1 的 B 细胞谱系缺陷显着影响类别转换重组 （CSR），导致免疫后 Mct1^f/fMb1^Cre 小鼠的 IgG 抗体反应受损。代谢通量显示，在 Mct1 缺陷型 B 细胞中，葡萄糖代谢在激活后从糖酵解显着重编程为氧化磷酸化。一致地，由于丙酮酸代谢物水平降低，激活诱导的胞苷脱氨酶 （AID） 在 Mct1 缺陷的 B 细胞中受到严重抑制。从机制上讲，需要 MCT1 来维持丙酮酸的最佳浓度，以确保 H3K27 的充分乙酰化，从而在活化的 B 细胞中增加 AID 的转录。临床上，我们发现系统性红斑狼疮患者 MCT1 表达水平显著上调，Mct1 缺乏可以缓解 bm12 诱导的小鼠狼疮模型的症状。总的来说，这些结果表明，通过表观遗传依赖性 AID 转录，IgG 抗体 CSR 需要 MCT1 介导的丙酮酸代谢，揭示了 MCT1 是疫苗开发和 SLE 疾病治疗的潜在靶点。