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ResearchIn-Press PreviewImmunologyMetabolism Open Access | 10.1172/JCI201325

SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway

Fabrizia Bonacina,1 Claudio Procaccini,2 Marta Iaia,1 Arianna Moretti,1 Monika Svecla,3 Silvia Pedretti,1 Jeroen F.J. Bogie,4 Giovani Battista Vingiani,1 Annalisa Moregola,1 Francesca Genova,1 Claudia Russo,2 Giusy De Rosa,2 Claudia La Rocca,2 Giada Mondanelli,5 Marco Gargaro,5 Nico Mitro,1 Giuseppe Matarese,2 and Giuseppe Danilo Norata1

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

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1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Procaccini, C. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Iaia, M. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Moretti, A. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Svecla, M. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Pedretti, S. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Bogie, J. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Vingiani, G. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Moregola, A. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Genova, F. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Russo, C. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by De Rosa, G. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by La Rocca, C. in: PubMed | Google Scholar

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Mondanelli, G. in: PubMed | Google Scholar |

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Gargaro, M. in: PubMed | Google Scholar |

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Mitro, N. in: PubMed | Google Scholar |

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Matarese, G. in: PubMed | Google Scholar |

1Department of Excellence of Pharmacological and Biomolecular Sciences “Rodo, Università degli Studi di Milano, Milan, Italy

2Laboratorio di Immunologia, Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" - Consiglio Nazionale delle Ricerche (IEOMI-CNR), Naples, Italy

3Deutsches Herzzentrum der Charité (DHZC) – Charité-Universitätsmedizin, Berlin, Germany

4Department of immunology and Infection, Hasselt University, Diepenbeek, Belgium

5Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Find articles by Norata, G. in: PubMed | Google Scholar |

Published July 21, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201325.
Copyright © 2026, Bonacina et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 21, 2026 - Version history
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Abstract

Regulatory T cells (Tregs) maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports Treg migration, lipid metabolism sustains their suppressive phenotype. Here, we identify the sterol regulatory element–binding protein 1c (SREBP1c) as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro-derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.

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