TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation
What this study shows
Sustained TCR signaling activates mTORC1, which boosts translation of the TET2 (and likely TET3) DNA-demethylation enzymes; this demethylates the Foxp3 TSDR enhancer and epigenetically locks in stable Foxp3 expression in regulatory T cells. In vivo mTORC1 inactivation increases methylated-TSDR Foxp3+ T cells, confirming the pathway's physiological relevance.
Abstract
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Regulatory T (Treg) cell differentiation and function rely on stable expression of the master transcription factor Foxp3. While Foxp3 expression is epigenetically stabilized through DNA demethylation of an enhancer (the Treg-specific demethylated region, TSDR), the mechanisms underlying this process remain unclear. Here, we show that strong and sustained T cell receptor (TCR) signaling promotes TSDR demethylation, stabilizes Foxp3 expression, and confers suppressive activity in in vitro-induced Treg (iTreg) cells through activation of mTORC1.
Read the full abstract on PubMed →At a glance
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse; in vitro-induced regulatory T cells (iTreg)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse; in vitro-induced regulatory T cells (iTreg) |
| Journal | Proceedings of the National Academy of Sciences |
| Year | 2026 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1073/pnas.2612904123 · PMID 42809396 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
People in the Atlas
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First author identifying how TCR-driven mTORC1 signaling epigenetically locks in Foxp3 expression in regulatory T cells
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Senior author; laboratory head studying regulatory T cell differentiation and immune tolerance
More: 10 other authors
No profile yet: Nakajima A, Kobayashi T, Ohno M, Wei Y, Hasegawa T, Hayatsu N, Hirayama S, Tsukada YI, Hirao A, Murata S
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | mTORC1 inactivation (genetic/pharmacological) and TET2/TET3 deficiency in TCR-stimulated iTreg cells |
| Target | mTORC1 -> translational control of TET2/TET3 -> Foxp3 TSDR demethylation |
| Model | Mouse (in vitro-induced regulatory T cells, with in vivo confirmation) |
| Effect | TCR-driven mTORC1 raises TET2/TET3 translation to demethylate the Foxp3 TSDR enhancer and epigenetically stabilize Foxp3 expression; mTORC1 inactivation increases methylated-TSDR Foxp3+ T cells. |
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