title: Conditional deletion of ferritin h in mice reduces B and T lymphocyte populations.
abstract: The immune system and iron availability are intimately linked as appropriate iron supply is needed for cell proliferation, while excess iron, as observed in hemochromatosis, may reduce subsets of lymphocytes. We have tested the effects of a ferritin H gene deletion on lymphocytes. Mx-Cre mediated conditional deletion of ferritin H in bone marrow reduced the number of mature B cells and peripheral T cells in all lymphoid organs. FACS analysis showed an increase in the labile iron pool, enhanced reactive oxygen species formation and mitochondrial depolarization. The findings were confirmed by a B-cell specific deletion using Fth(lox/lox) ; CD19-Cre mice. Mature B cells were strongly under-represented in bone marrow and spleen of the deleted mice, whereas pre-B and immature B cells were not affected. Bone marrow B cells showed increased proliferation as judged by the number of cells in S and G2/M phase as well as BrdU incorporation. Upon in vitro culture with B-cell activating factor of the tumor necrosis factor family (BAFF), ferritin H-deleted spleen B cells showed lower survival rates than wild type cells. This was partially reversed with iron-chelator deferiprone. The loss of T cells was also confirmed by a T cell-specific deletion in Fth(lox/lox) ;CD4-Cre mice. Our data show that ferritin H is required for B and T cell survival by actively reducing the labile iron pool. They further suggest that natural B and T cell maturation is influenced by intracellular iron levels and possibly deregulated in iron excess or deprivation.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Sciences de la Vie (SV), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Liviu
authors.initials: L
authors.lastname: Vanoaica
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Sciences de la Vie (SV), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Larry
authors.initials: L
authors.lastname: Richman
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Maike
authors.initials: M
authors.lastname: Jaworski
authors.affiliation: Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Darshan
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Sciences de la Vie (SV), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Kühn
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics*; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D001052:Apoferritins; D007501:Iron