Iron has long been established as a critical mediator of T cell development and proliferation. However, the mechanisms by which iron controls CD4 T cell activation and expansion remain poorly understood. In this study, we show that stimulation of CD4 T cells from C57BL/6 mice not only decreases total and labile iron levels but also leads to changes in the expression of iron homeostatic machinery. Additionally, restraining iron availability in vitro severely inhibited CD4 T cell proliferation and cell cycle progression. Although modulating cellular iron levels increased IL-2 production by activated T lymphocytes, CD25 expression and pSTAT5 levels were decreased, indicating that iron is necessary for IL-2R-mediated signaling. We also found that iron deprivation during T cell stimulation negatively impacts mitochondrial function, which can be reversed by iron supplementation. In all, we show that iron contributes to activation-induced T cell expansion by positively regulating IL-2R signaling and mitochondrial function.
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