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Cited by 16T-cell and B-cell ImmunologyIon Channels and ReceptorsPsoriasis: Treatment and Pathogenesis

Differentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca 2+ influx

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Min, Hyungyu, Kim, Wooseob, Hong, Sehoon, Lee, Sungkyu, Jeong, Jinguk, Kim, Seyun, Seong, Rho H.·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2121520119PMC PMC9271192
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Abstract

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 2+ 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 2+ mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca 2+ influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.

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Cited by

Sorted by citations

Authors
Min, H., Kim, W., Hong, S., Lee, S., Jeong, J., Kim, S., & Seong, R. H.
Affiliations
  • Seoul National University (KR)
  • Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
  • Korea Advanced Institute of Science and Technology (KR)
Corresponding author
  • Kim, Seyun
  • Seong, Rho H.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-07
Volume
119
Issue
27
Pages
e2121520119-e2121520119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2121520119
PMC
PMC9271192
OpenAlex
W4283762492
Cited by
16
References
5
Citations by year
2026: 4 · 2025: 4 · 2024: 7 · 2023: 1
FWCI
1.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Research Foundation of Korea (NRF-2021R1A2B5B03002202, NRF-2014M3A9D5A01073789, NRF-2018R1A5A1024261, NRF-2020R1A2C3005765)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
effector regulatory T cells, inositol polyphosphate multikinase, inositol tetrakisphosphate, inositol pentakisphosphate, store-operated calcium entry, T cell receptor signaling, calcium influx, immune homeostasis, peripheral tolerance
MeSH terms
Animals, Calcium, Cell Differentiation, Homeostasis, Polyphosphates, Receptors, Antigen, T-Cell, Phosphotransferases (Alcohol Group Acceptor), T-Lymphocytes, Regulatory, Mice, Nuclear Receptor Subfamily 1, Group F, Member 3

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