Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for maturation of the antibody response. Epigenetic factors, such as histone deacetylases (HDACs), would underpin B cell differentiation stage–specific AID expression. Here, we showed that NAD⁺-dependent class III HDAC sirtuin 1 (Sirt1) is highly expressed in resting B cells and down-regulated by stimuli inducing AID. B cell Sirt1 down-regulation, deprivation of NAD⁺ cofactor, or genetic Sirt1 deletion reduced deacetylation of Aicda promoter histones, Dnmt1, and nuclear factor–κB (NF-κB) p65 and increased AID expression. This promoted class-switched and hypermutated T-dependent and T-independent antibody responses or led to generation of autoantibodies. Genetic Sirt1 overexpression, Sirt1 boost by NAD⁺, or allosteric Sirt1 enhancement by SRT1720 repressed AID expression and CSR/SHM. By deacetylating histone and nonhistone proteins (Dnmt1 and NF-κB p65), Sirt1 transduces metabolic cues into epigenetic changes to play an important B cell–intrinsic role in modulating antibody and autoantibody responses.

激活诱导的胞苷脱氨酶 (AID) 介导免疫球蛋白类别转换 DNA 重组 (CSR) 和体细胞超突变 (SHM)，这是抗体反应成熟的关键过程。表观遗传因素，例如组蛋白脱乙酰酶 (HDAC)，将支持 B 细胞分化阶段特异性 AID 表达。在这里，我们发现 NAD ⁺依赖性 III 类 HDAC Sirtuin 1 (Sirt1) 在静息 B 细胞中高表达，并被诱导 AID 的刺激下调。 B 细胞 Sirt1 下调、NAD ⁺辅因子缺失或遗传 Sirt1 缺失会减少Aicda启动子组蛋白、Dnmt1 和核因子 -κB (NF-κB) p65 的脱乙酰化，并增加 AID 表达。这促进了类别转换和超突变的 T 依赖性和 T 独立抗体反应，或导致自身抗体的产生。 Sirt1 遗传过度表达、NAD ⁺增强 Sirt1 或 SRT1720 增强 Sirt1 变构抑制了 AID 表达和 CSR/SHM。通过使组蛋白和非组蛋白（Dnmt1 和 NF-κB p65）去乙酰化，Sirt1 将代谢线索转化为表观遗传变化，从而在调节抗体和自身抗体反应中发挥重要的 B 细胞内在作用。