Adaptive immunity requires the expansion of high-affinity lymphocytes from a heterogeneous pool. Whereas current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Here, we identify nicotinamide adenine dinucleotide (NAD) biosynthesis as a biochemical hub for the T cell receptor affinity–dependent metabolome. Through this central anabolic role, we found that NAD biosynthesis governs a quiescence exit checkpoint, thereby pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities, and enhancing NAD biosynthesis permits the expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) could predict division potential for both T and B cells, before the first division, unmixing proliferative heterogeneity. We believe that this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.

中文翻译：

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单细胞 NAD(H) 水平预测克隆淋巴细胞扩增动态

适应性免疫需要从异质池中扩增高亲和力淋巴细胞。尽管当前的模型通过信号转导解释了这一点，但我们假设抗原亲和力调节离散的代谢途径以许可克隆淋巴细胞动力学。在这里，我们将烟酰胺腺嘌呤二核苷酸 (NAD) 生物合成确定为 T 细胞受体亲和力依赖性代谢组的生化中心。通过这种中心合成代谢作用，我们发现 NAD 生物合成控制着一个静止退出检查点，从而调节增殖速度。使细胞 NAD(H) 正常化同样可以使亲和力的增殖正常化，并且增强 NAD 生物合成允许较低亲和力克隆的扩增。此外，NAD(H) 的单细胞差异可以预测 T 细胞和 B 细胞在第一次分裂之前的分裂潜力，从而消除增殖异质性。我们相信，这支持了更广泛的范式，其中复杂的信号网络汇聚在代谢途径上以控制单细胞行为。