School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
Proc Natl Acad Sci U S A. 2022 Jul 5;119(27):e2121520119. doi: 10.1073/pnas.2121520119. Epub 2022 Jul 1.
Activated Foxp3 regulatory T (Treg) cells differentiate into effector Treg (eTreg) cells to maintain peripheral immune homeostasis and tolerance. T cell receptor (TCR)-mediated induction and regulation of store-operated Ca entry (SOCE) is essential for eTreg cell differentiation and function. However, SOCE regulation in Treg cells remains unclear. Here, we show that inositol polyphosphate multikinase (IPMK), which generates inositol tetrakisphosphate and inositol pentakisphosphate, is a pivotal regulator of Treg cell differentiation downstream of TCR signaling. IPMK is highly expressed in TCR-stimulated Treg cells and promotes a TCR-induced Treg cell program. IPMK-deficient Treg cells display aberrant T cell activation and impaired differentiation into RORγt Treg cells and tissue-resident Treg cells. Mechanistically, IPMK controls the generation of higher-order inositol phosphates, thereby promoting Ca mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.
活化的叉头框蛋白 3（Foxp3）调节性 T（Treg）细胞分化为效应性 Treg（eTreg）细胞，以维持外周免疫稳态和耐受。T 细胞受体（TCR）介导的储存操作钙内流（SOCE）的诱导和调节对于 eTreg 细胞分化和功能至关重要。然而，Treg 细胞中的 SOCE 调节仍不清楚。在这里，我们表明，肌醇多磷酸激酶（IPMK），其生成肌醇四磷酸和肌醇五磷酸，是 TCR 信号下游 Treg 细胞分化的关键调节因子。IPMK 在 TCR 刺激的 Treg 细胞中高度表达，并促进 TCR 诱导的 Treg 细胞程序。IPMK 缺陷的 Treg 细胞表现出异常的 T 细胞活化和受损的分化为 RORγt Treg 细胞和组织驻留 Treg 细胞。在机制上，IPMK 控制更高阶肌醇磷酸的产生，从而促进钙动员和 Treg 细胞效应功能。我们的发现确定了 IPMK 是 TCR 介导的 Ca 内流的关键调节剂，并强调了 IPMK 在 Treg 细胞介导的免疫稳态中的重要性。
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