Regulation of intracellular iron metabolism by ferritin H chain controls regulatory T-cell function

Regulatory (TREG) T cells develop under a genetic program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Sustained FOXP3 transcription, enforced via cytosine demethylation of Cytosine-phosphate-guanine (CpG)-rich sequences at FOXP3 conserved non-coding sequences (CNS), is essential to support TREG cell function and lineage maintenance. Cytosine demethylation is catalyzed by redox-based reactions whereby the ten-eleven translocation (TET) family of dioxygenases use iron (Fe) as an essential co-factor. Having established that human and mouse TREG cells express relatively high levels of Fe-regulatory genes, we found that ferritin H chain (FTH) is essential to support TREG cell survival and lineage stability. Genetic loss of Fth function in TREG cells compromises immune homeostasis and exacerbates the severity of autoimmune neuroinflammation as well as infectious diseases such as malaria, while repressing tumor progression. Mechanistically, FTH sustains Fe-redox homeostasis and promotes TREG cells lineage maintenance. The latter is associated with demethylation of CpG-rich sequences at Foxp3 CNS1 and 2 and with sustained Foxp3 transcription, attributed to regulation of TET activity via the ferroxidase activity of FTH. In conclusion, regulation of Fe redox activity by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathologic outcome of immune-mediated inflammation.