Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease.治疗免疫失调的新兴策略多以小分子抑制剂靶向抗原受体下游的正向调控激酶。本研究为一类全新替代疗法提供了实验依据：在成熟T淋巴细胞中抑制负调控型肌醇激酶Itpkb，可在抗原受体激活后提升细胞内钙离子水平，进而引发T细胞死亡。本研究利用Itpkb条件性敲除小鼠与低分子量（LMW）Itpkb抑制剂开展实验，结果证实Itpkb可通过其产物肌醇四磷酸（IP4）抑制淋巴细胞表面的Orai1/Stim1钙通道。通过药理学手段抑制Itpkb，或对其进行基因敲除，均可升高细胞内钙离子浓度，诱导Fas配体（Fas ligand, FasL）与Bim蛋白的表达，最终触发T细胞凋亡。在活体动物中，敲除Itpkb或使用Itpkb抑制剂处理，可阻断T细胞依赖性抗体应答，并能够预防大鼠体内T细胞介导的关节炎。上述实验数据证实Itpkb是T细胞激活过程中的关键调控介质，同时提示抑制Itpkb可作为治疗自身免疫疾病的全新策略。