肌醇多磷酸多激酶通过控制Akt-mTOR信号传导来调节Th1和Th17细胞分化。 - Suppr | 超能文献

Abstract

Activated proinflammatory T helper (Th) cells, including Th1 and Th17 cells, drive immune responses against pathogens and contribute to autoimmune diseases. We show that the expression of inositol polyphosphate multikinase (IPMK), an enzyme essential for inositol phosphate metabolism, is highly induced in Th1 and Th17 subsets. Deletion of IPMK in CD4 T cells leads to diminished Th1- and Th17-mediated responses, reducing resistance to Leishmania major and attenuating experimental autoimmune encephalomyelitis. IPMK-deficient CD4 T cells show impaired activation and Th17 differentiation, linked to the decreased activation of Akt, mTOR, and STAT3. Mechanistically, IPMK functions as a phosphatidylinositol 3-kinase to regulate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P) production, promoting T cell activation and effector functions. In IPMK-deficient CD4 T cells, T cell receptor-stimulated PtdIns(3,4,5)P generation is abolished by wortmannin, suggesting IPMK acts in a wortmannin-sensitive manner. These findings establish IPMK as a critical regulator of Th1 and Th17 differentiation, underscoring its role in maintaining immune homeostasis.

摘要

活化的促炎性辅助性T细胞（Th），包括Th1和Th17细胞，驱动针对病原体的免疫反应并促成自身免疫性疾病。我们发现，肌醇多磷酸多激酶（IPMK）（一种肌醇磷酸代谢所必需的酶）的表达在Th1和Th17亚群中被高度诱导。CD4 T细胞中IPMK的缺失导致Th1和Th17介导的反应减弱，降低了对硕大利什曼原虫的抵抗力并减轻了实验性自身免疫性脑脊髓炎。缺乏IPMK的CD4 T细胞显示出活化受损和Th17分化受损，这与Akt、mTOR和STAT3的活化降低有关。从机制上讲，IPMK作为一种磷脂酰肌醇3激酶来调节磷脂酰肌醇（3,4,5）-三磷酸（PtdIns(3,4,5)P）的产生，促进T细胞活化和效应功能。在缺乏IPMK的CD4 T细胞中，渥曼青霉素可消除T细胞受体刺激的PtdIns(3,4,5)P生成，这表明IPMK以渥曼青霉素敏感的方式发挥作用。这些发现确立了IPMK作为Th1和Th17分化的关键调节因子，强调了其在维持免疫稳态中的作用。