As an essential biometal, iron is vital for maintaining normal physiological function. Studies on iron deficiency or iron overload have shown the importance of iron homeostasis in immune defense against microbial infections. Iron deficiency is known to impair adaptive immune functions ranging from immunoglobulin secretion, cytokine production, and lymphocyte homeostasis. Iron has also been implicated in T cell development and proliferation. In fact, iron deficient patients exhibit decreased peripheral T cell numbers and diminished T cell function compared to healthy people. However, the mechanisms by which iron is regulated during T cell-mediated immune responses remain poorly understood. Here, we show that activated T cells decrease intracellular iron levels despite increasing their expression of iron import (transferrin receptor 1) and storage (ferritin) proteins. And TCR signaling is responsible for the decreased iron level of activated T cells. Additionally, restraining iron availability in vitro severely inhibits CD4 T cell proliferation, which appears to be due to altered IL-2 receptor signaling. Furthermore, we found that treatment with iron chelators during stimulation impairs mitochondrial function in activated CD4 T cells, which can be reversed by iron supplementation. In all, we show that iron contributes to activation-induced T cell expansion by positively regulating IL-2 receptor signaling and mitochondrial function.
