ABCB7 deficiency causes ferroptosis in peripheral T cells

Abstract ABCB7 exports iron-sulfur (Fe-S) clusters from the mitochondria into the cytoplasm. Conditional deletion of ABCB7 revealed that it is required for peripheral T cell homeostasis. CD4-cre ABCB7 cKO mice have normal thymic development, but a severe reduction in peripheral T cell numbers. A majority of the peripheral T cells in the ABCB7 cKO mice were recent thymic emigrants (RTEs), indicating a loss of more mature T cells in the periphery. T cell maturation markers were found to be normal and stimulation of ABCB7 cKO RTEs revealed normal levels of TNFα production. These data indicate that the loss of peripheral T cells in CD4-cre ABCB7 cKO mice was not due to a defect in development or maturation but a defect in peripheral homeostasis. ABCB7-deficient T cells did not have evidence of elevated apoptosis. We demonstrated iron accumulation was occurring in ABCB7-deficient peripheral T cells using the metal-specific dye Phen Green SK. Additionally, lipid peroxides levels were elevated in the ABCB7 cKO T cells. Lipid peroxides are a hallmark of ferroptosis, an iron-dependent form of regulated cell death. Expression of GPX4, the master regulator of ferroptosis, was normal in ABCB7 cKO T cells. In addition, levels of glutathione, which counteracts lipid peroxides were found to be normal, indicating the ferroptosis protection pathway was intact and that the iron overload was causing ferroptosis. Interestingly, treatment with the iron chelator deferoxamine did not rescue peripheral T cells in the CD4-cre ABCB7 cKO mice. Vitamin E, a potent antioxidant, also failed to rescue peripheral T cell homeostasis. Thus, ABCB7 is required to maintain iron homeostasis and its loss leads to peripheral T cell ferroptosis.