The EMBO journal · 2024
Ferritin heavy chain supports stability and function of the regulatory T cell lineage.
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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
Аннотация
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.