ArticleFrontiers in immunology2025
Differential regulation of Treg stability in human naïve and effector Treg subsets by TGFβ-signaling via ARKADIA-SKI axis.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Targeting regulatory T cells in the prostate cancer microenvironment: From mechanisms to therapeutics (Review).Molecular medicine reports · 2026Review
- Regulatory T cells in pregnancy disorders: a multi-dimensional framework for biomarkers and therapeutic strategies.Frontiers in immunology · 2026Review
- Increased phenotypic and functional stability of human allospecific induced Tregs is associated with Vitamin C-mediatedFrontiers in immunology · 2026Article
- Regulatory T cells in cardiac allograft vasculopathy: from mechanistic insights to clinical tolerance.Frontiers in immunology · 2026Review
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Authors and funding
11 authors.
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Abstract
Introduction: The human FOXP3 Methods: Human naïve and effector Treg cells were isolated from healthy donors using flow cytometry. Different subsets of Treg cells were treated with a TGFβ inhibitor or genetically modified to express SKI or ARKADIA via lentiviral transduction. Treg cell phenotype, stability and signaling regulation were analyzed using flow cytometry, western blotting, transcriptomic and meta-analyses. The functionality of Treg cells was analyzed by Results: We find that the TGFβ signaling is differentially regulated in Treg subsets, with higher activity in the naïve Treg subset. Blockade of TGFβ pathway destabilizes both naïve and effector Treg cells, disrupting their immunosuppressive functions, with effector Treg cells being more susceptible. Further analysis shows that naïve Treg cells express lower levels of SKI protein, a negative regulator of TGFβ signaling suppressed by TGFβ-induced protein degradation. SKI overexpression destabilizes Treg cells and disrupts their immune suppressive function. Transcriptomic and meta-analyses reveal that TGFβ blockade and SKI overexpression commonly modulate pathways crucial for Treg to effector T cell conversion, downregulating Treg signature genes and upregulating effector T cell markers, which are validated as potential SKI targets. Importantly, overexpression of ARKADIA, an E3 ubiquitin ligase of SKI, efficiently reduces SKI levels, enhancing Treg cell stability and functionality under both TGFβ inhibition and chronic proinflammatory cytokine stimulation. Conclusion: Our results identify a previously unrecognized role of the TGFβ-ARKADIA-SKI axis in regulating the stability and functionality of human Treg subsets, highlighting novel strategies for harnessing TGFβ-associated pathways to stabilize human Treg cells for clinical applications.
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