biostudies-literatureMin HNational Research Foundation of Koreae2121520119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9271192biostudies-literatureUnknown119(27)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 Ca²⁺ 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<sup>+<Proceedings of the National Academy of Sciences of the United States of AmericaDifferentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca²⁺ influx.PMC9271192NRF-2020R1A2C3005765NRF-2021R1A2B5B03002202NRF-2018R1A5A1024261NRF-2014M3A9D5A01073789Kim SLee SJeong JMin HKim WSeong RHHong SfalseDifferentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca²⁺ influx.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 Ca²⁺ 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<sup>+<2022-01-01T00:00:00Z2022 Jul2025-04-21T15:23:49.835Z2025-04-21T15:23:49.835ZS-EPMC92711923577654310.1073/pnas.2121520119