Researchers here report a novel mechanisms by which aging impairs the immune system. The spleen is an immune organ, an important location where immune cells congregate to communicate with one another and coordinate the immune response to pathogens. The spleen is also responsible for filtering damaged and worn red blood cells from the circulation. Unfortunately the aged spleen accumulates too much iron and metabolic waste as a result of reduced efficiency in clearing out those unwanted red blood cells. Exposure to this aged spleen environment is here shown to degrade the efficacy of T cells of the adaptive immune system.
Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging.
Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice.
This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.
Link: https://doi.org/10.1038/s43587-025-00981-4
View the full article at FightAging
