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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Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients.PLoS One. 2013 Dec 23;8(12):e83811. doi: 10.1371/journal.pone.0083811. eCollection 2013. PLoS One. 2013. PMID: 24376757 Free PMC article.
Dysregulation of IL-2/IL-2R system alters proliferation of early activated CD4+ T cell subset in patients with end-stage renal failure.Clin Nephrol. 2005 Jan;63(1):8-21. doi: 10.5414/cnp63008. Clin Nephrol. 2005. PMID: 15678692
CD25 and Protein Phosphatase 2A Cooperate to Enhance IL-2R Signaling in Human Regulatory T Cells.J Immunol. 2019 Jul 1;203(1):93-104. doi: 10.4049/jimmunol.1801570. Epub 2019 May 13. J Immunol. 2019. PMID: 31085588
Signal transduction in CD4+CD25+ regulatory T cells: CD25 and IL-2.Front Biosci. 2006 Jan 1;11:921-7. doi: 10.2741/1848. Front Biosci. 2006. PMID: 16146782 Review.
Biology of the interleukin-2 receptor.Adv Immunol. 1998;70:1-81. doi: 10.1016/s0065-2776(08)60386-7. Adv Immunol. 1998. PMID: 9755337 Review.