TY - JOUR
T1 - Ferritin heavy chain supports stability and function of the regulatory T cell lineage
AU - Wu, Qian
AU - Carlos, Ana Rita
AU - Braza, Faouzi
AU - Bergman, Marie-Louise
AU - Kitoko, Jamil Z.
AU - Bastos-Amador, Patricia
AU - Cuadrado, Eloy
AU - Martins, Rui
AU - Oliveira, Bruna Sabino
AU - Martins, Vera C.
AU - Scicluna, Brendon P.
AU - Landry, Jonathan J. M.
AU - Jung, Ferris E.
AU - Ademolue, Temitope W.
AU - Peitzsch, Mirko
AU - Almeida-Santos, Jose
AU - Thompson, Jessica
AU - Cardoso, Silvia
AU - Ventura, Pedro
AU - Slot, Manon
AU - Rontogianni, Stamatia
AU - Ribeiro, Vanessa
AU - Domingues, Vital Da Silva
AU - Cabral, Inês A.
AU - Weis, Sebastian
AU - Groth, Marco
AU - Ameneiro, Cristina
AU - Fidalgo, Miguel
AU - Wang, Fudi
AU - Demengeot, Jocelyne
AU - Amsen, Derk
AU - Soares, Miguel P.
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024/4/16
Y1 - 2024/4/16
N2 - 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.
AB - 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.
KW - FOXP3
KW - Ferritin Heavy Chain
KW - Iron Metabolism
KW - Regulatory T Cells
KW - Ten–eleven Translocation Enzymes
UR - http://www.scopus.com/inward/record.url?scp=85188117216&partnerID=8YFLogxK
U2 - 10.1038/s44318-024-00064-x
DO - 10.1038/s44318-024-00064-x
M3 - Article
C2 - 38499786
SN - 0261-4189
VL - 43
SP - 1445
EP - 1483
JO - EMBO Journal
JF - EMBO Journal
IS - 8
ER -