Heme toxicity in the aged spleen impairs T-cell immunity through iron deprivation
Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with other immune and stromal cells. Here, we investigated how the tissue microenvironment influences T-cell aging trajectories. Spleen-derived lymphocytes exhibited greater 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 CD39. T cells survived the hostile microenvironment of the aged spleen by restricting iron uptake and maintaining low labile iron pools. Nevertheless, 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, and highlight the bidirectional relationship between T cells and their microenvironment. Understanding these mechanisms will inform strategies to enhance immune responses in the elderly.