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Updated: Sep 6, 2025

In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol
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In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol

Published on: December 30, 2016

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Differentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca2+

Hyungyu Min1, Wooseob Kim1, Sehoon Hong2

  • 1School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea.

Proceedings of the National Academy of Sciences of the United States of America
|July 1, 2022
PubMed

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+ Treg cells and tissue-resident Treg cells. Mechanistically, IPMK controls the generation of higher-order inositol phosphates, thereby promoting Ca2+ mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca2+ influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.

Keywords:
Ca2+ influxT cell receptor signalinginositol phosphateinositol polyphosphate multikinaseregulatory T cells

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