Heme Toxicity In The Aged Spleen Impairs T-cell Immunity Through Iron Deprivation

Aging profoundly impacts T cell immunity, compromising vaccine responses, susceptibility to infections, and immunosurveillance. Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with other immune and stromal cells. This study investigates how a tissue’s microenvironment influences T cell aging trajectories, following our discovery of varying rates of T cell aging within a single host. Spleen-derived lymphocytes exhibited functional decline compared to those from lymph nodes, with proteomic analysis revealing increased expression of heme detoxification and iron storage proteins in aged spleen-derived lymphocytes. Exposure to the aged spleen microenvironment or to heme induced multiple aging phenotypes in young lymphocytes, including reduced proliferation and upregulation of the ectonucleotidases CD39 and CD73. Mechanistically, we show that T cells survive the hostile microenvironment of the aged spleen by restricting iron uptake and maintaining low labile iron pools to resist ferroptosis. Finally, vaccination responses in aged mice were enhanced by timed iron infusions. Our findings underscore a trade-off between T cell survival and function in the aged host. Recent studies show how Dysfunctional T cells induce premature aging phenotypes in multiple solid organs of a young host. Our findings highlight the bidirectional relationship between T cells and their aging microenvironment. Understanding these mechanisms will inform strategies to enhance immune responses in the elderly.