Details

Autor(en) / Beteiligte

• Wu, Qian
• Carlos, Ana Rita
• Braza, Faouzi
• Bergman, Marie-Louise
• Kitoko, Jamil Z
• Bastos-Amador, Patricia
• Cuadrado, Eloy
• Martins, Rui
• Oliveira, Bruna Sabino
• Martins, Vera C
• Scicluna, Brendon P
• Landry, Jonathan JM
• Jung, Ferris E
• Ademolue, Temitope W
• Peitzsch, Mirko
• Almeida-Santos, Jose
• Thompson, Jessica
• Cardoso, Silvia
• Ventura, Pedro
• Slot, Manon
• Rontogianni, Stamatia
• Ribeiro, Vanessa
• Domingues, Vital Da Silva
• Cabral, Inês A
• Weis, Sebastian
• Groth, Marco
• Ameneiro, Cristina
• Fidalgo, Miguel
• Wang, Fudi
• Demengeot, Jocelyne
• Amsen, Derk
• Soares, Miguel P

Titel

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Ist Teil von

• The EMBO journal, 2024-04, Vol.43 (8), p.1445-1483

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2024

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten–eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation. Synopsis Sustained FOXP3 transcription is central to the development and maintenance of regulatory T (TREG) cells. This study shows that the regulation of iron metabolism by ferritin heavy chain (FTH) influences FOXP3 expression and TREG cell lineage stability under homeostatic and pathological conditions. Human and mouse TREG cells express FTH at high levels. FTH sustains TREG cell lineage stability. FTH regulates FOXP3 methylation and transcription through supporting the enzymatic activity of the TET family of iron-dependent dioxygenases. FTH expression in TREG cells limits inflammation and supports tumor progression. Iron metabolism promotes FOXP3 transcription in regulatory T cells by supporting TET enzymatic activity.