T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not up-regulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1^low phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1^high and MTH1^low activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.

T 细胞驱动的疾病在全球范围内造成相当大的发病率和残疾，因此迫切需要新的靶向治疗。癌细胞和活化的 T 细胞都具有改变的氧化还原平衡，并上调 DNA 修复蛋白 MTH1，该蛋白净化氧化核苷酸库以避免 DNA 损伤和细胞死亡。在此，我们认为活化 T 细胞中 MTH1 的上调与其氧化还原状态相关，但发生在 ROS 水平增加之前，挑战了既定的 MTH1 增加是对 ROS 状态增加的直接反应的概念。我们还提出了活化 T 细胞中 MTH1 水平的异质性，其中一小部分活化 T 细胞尽管活化和增殖但不会上调 MTH1。该研究表明，绝大多数活化的 T 细胞具有高 MTH1 水平，并且通过诱导 DNA 损伤和细胞周期停滞对 MTH1 抑制剂 TH1579 (Karonudib) 敏感。TH1579 进一步驱动存活的细胞到 MTH1氧化还原状态改变的^低表型。与已建立的免疫抑制剂硫唑嘌呤相反，TH1579 不影响静息 T 细胞，并且观察到其他主要免疫细胞类型对其功能没有敏感性。最后，我们证明了在实验性自身免疫性脑脊髓炎小鼠模型中的治疗效果。总之，我们证明了存在 MTH1^高和 MTH1^低活化 T 细胞的概念，以及 TH1579 对 MTH1 的抑制选择性地抑制了促炎性活化 T 细胞。因此，TH1579 对 MTH1 的抑制作用可作为针对自身免疫性疾病（例如多发性硬化症）中自身反应性 T 细胞的新型治疗选择。