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Browsing by Author "Demengeot, Jocelyne"

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  • Ferritin heavy chain supports stability and function of the regulatory T cell lineage
    Publication . 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
    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.
    2024-03Journal article Open access Show more
  • Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery
    Publication . Paiva, Ricardo S.; Lino, Andreia C.; Bergman, Marie-Louise; Caramalho, Íris; Sousa, Ana E.; Zelenay, Santiago; Demengeot, Jocelyne
    Most Forkhead box P3(+) (Foxp3(+)) CD4 regulatory T cell (Treg) precursors are newly formed thymocytes that acquire Foxp3 expression on antigen encounter in the thymus. Differentiation of Treg, however, can also occur in the periphery. What limits this second layer of self- and nonself-reactive Treg production in physiological conditions remains to be understood. In this work, we tested the hypothesis that, similarly to thymic Treg, the precursors of peripheral Treg are immature T cells. We show that CD4(+)CD8(-)Foxp3(-) thymocytes and recent thymic emigrants (RTEs), contrarily to peripheral naïve mature cells, efficiently differentiate into Treg on transfer into lymphopenic mice. By varying donor and recipient mice and conducting ex vivo assays, we document that the preferential conversion of newly formed T cells does not require intrathymic preactivation, is cell-intrinsic, and correlates with low and high sensitivity to natural inhibitors and inducers of Foxp3 expression, such as IL-6, T-cell receptor triggering, and TGF-β. Finally, ex vivo analysis of human thymocytes and peripheral blood T cells revealed that human RTE and newly developed T cells share an increased potential to acquire a FOXP3(bright)CD25(high) Treg phenotype. Our findings indicating that RTEs are the precursors of Tregs differentiated in the periphery should guide the design of Treg-based therapies.
    2013Journal article Open access Show more