Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4+ T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nuclear translocation, strongly reduces their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. TEPP-46 limits the development of both T helper 17 (Th17) and Th1 cells in vitro and ameliorates experimental autoimmune encephalomyelitis (EAE) in vivo. Overall, our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T cell-mediated inflammation and autoimmunity.

中文翻译：

---

丙酮酸激酶M2的药理激活抑制CD4 + T细胞的致病性并抑制自身免疫。

丙酮酸激酶（PK）催化糖酵解过程中磷酸烯醇丙酮酸转化为丙酮酸。PK同工型PKM2在基因转录和蛋白质磷酸化的调控中还具有其他作用。已经显示，PKM2可控制炎症反应中的巨噬细胞代谢重塑，但人们对其在T细胞生物学中的作用了解甚少。在这里，我们报告在体外激活后，小鼠和人类CD4 + T细胞中的PKM2上调，磷酸化和核积累。用TEPP-46处理T细胞，这是一种变构激活剂，可诱导PKM2四聚化并阻断其核易位，可通过抑制必需的信号通路并因此阻止糖酵解作用来大大降低其激活，增殖和细胞因子的产生。TEPP-46限制了体外T辅助细胞17（Th17）和Th1细胞的发育，并改善了体内实验性自身免疫性脑脊髓炎（EAE）。总体而言，我们的结果表明，PKM2的药理靶向可能代表T细胞介导的炎症和自身免疫的一种有价值的治疗方法。