Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P₂. They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.

调节性 T 细胞 (Tregs) 在维持外周耐受以防止自身免疫和限制合法免疫反应方面发挥着重要作用，这一特征在肿瘤微环境中被劫持，其中 Tregs 的募集通常通过抑制 T 效应细胞信号传导和肿瘤细胞杀伤来消除免疫监视. 在不影响 T 常规 (Tconv) 细胞活性的情况下对 Treg 活性进行药理学调整可能有益于治疗各种人类疾病。PIP4K2A、2B 和 2C 构成脂质激酶家族，可将 PtdIns5 P磷酸化为PtdIns(4,5) P ₂. 它们参与应激信号传导，在 p53-null 肿瘤中充当合成致死靶标，在小鼠中，PIP4K2C 的缺失导致迟发性过度炎症。因此，PIP4K2C 基因附近的人类单核苷酸多态性 (SNP) 与自身免疫性疾病的易感性有关。PIP4Ks 如何影响人类 T 细胞信号尚不清楚。使用离体人原代 T 细胞，我们发现 PIP4K 活性是 Treg 细胞信号传导和免疫抑制活性所必需的。Tregs 中 PIP4K 的遗传和药理学抑制减少了通过 PI3K、mTORC1/S6 和 MAPK 途径的信号传导，损害细胞增殖，并增加激活诱导的细胞死亡，同时保留 Tconv。PIP4K 和 PI3K 信号调节 Treg 主转录激活因子 FOXP3 和含有 PHD 和 RING 指结构域 1 (UHRF1) 的表观遗传信号蛋白泛素样蛋白的表达。我们的研究表明，PIP4K 的药理学抑制可以重新编程人类 Treg 身份，同时使 Tconv 细胞信号传导和 T 辅助细胞分化在很大程度上保持完整，从而可能增强整体免疫活性。