Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). T_H17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing T_H17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of T_H17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

促进丙酮酸激酶亚型 PKM2 代谢活性的小分子（例如 TEPP-46 和 DASA-58）可限制肿瘤发生和炎症。为了了解这些化合物如何改变 T 细胞功能，我们在模拟多发性硬化症 (MS) 的 T 细胞介导的自身免疫小鼠模型中评估了它们的治疗活性。 T _H 17 细胞被认为在一定程度上通过产生两种促炎细胞因子来协调 MS 病理：白细胞介素 17 (IL-17) 和 GM-CSF。我们发现 TEPP-46 和 DASA-58 都抑制了产生 IL-17 的 T _H 17 细胞的发育，但增加了产生 GM-CSF 的细胞的产生。这种转变将疾病病理从脊髓转移到大脑。此外，我们发现 PKM2 的激活会干扰 TGF-β1 信号传导，而这对于 T _H 17 和调节性 T 细胞的发育是必需的。总的来说，我们的数据阐明了 PKM2 激活剂在 MS 样疾病中的治疗潜力以及这些药物如何改变 T 细胞功能。