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SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway
Fabrizia Bonacina1, Claudio Procaccini2, Marta Iaia1
1Department of Excellence of Pharmacological and Biomolecular Sciences "Rodo, Università degli Studi di Milano, Milan, Italy.
The Journal of Clinical Investigation
|July 21, 2026
Summary
Sterol regulatory element-binding protein 1c (SREBP1c) is crucial for regulatory T cell (Treg) function. It links lipid metabolism to immune suppression by maintaining phospholipid homeostasis and adenosine signaling.
Area of Science:
- Immunology
- Cellular Metabolism
- Molecular Biology
Background:
- Regulatory T cells (Tregs) are vital for immune tolerance.
- Treg function is closely linked to cellular metabolism, with glycolysis supporting migration and lipid metabolism sustaining suppressive phenotypes.
Purpose of the Study:
- To identify key regulators of Treg immunobiology.
- To investigate the role of sterol regulatory element-binding protein 1c (SREBP1c) in Treg function and metabolism.
Main Methods:
- Analysis of Srebp1c-deficient mice Tregs.
- Transcriptomic and lipidomic analyses.
- In vitro Treg differentiation and functional assays.
- Pharmacological inhibition of cytosolic phospholipase A2 (cPLA2α).
Main Results:
- Srebp1c deficiency impairs Treg suppressive function, reduces Treg frequencies, and diminishes functional marker expression.
- Srebp1c-deficient Tregs exhibit metabolic rewiring toward glycolysis and defective phospholipid remodeling.
- Impaired lipid composition in Srebp1c-deficient Tregs reduces CD73 expression and adenosine-mediated immunosuppression.
- Inhibition of cPLA2α restores Treg function and adenosine signaling.
Conclusions:
- SREBP1c is a critical regulator of Treg immunobiology, acting as an immunometabolic checkpoint.
- SREBP1c links lipid metabolism to adenosine-dependent Treg suppression by maintaining phospholipid homeostasis.
- Targeting SREBP1c or related pathways may offer therapeutic strategies for immune modulation.
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