Ron-Harel, N.; Ezuz, D.; Ombashe, H.; Wattad, L.; atar, O.

Ageing profoundly impacts T cell immunity, compromising vaccine responses, susceptibility to infections, and immunosurveillance. Mechanisms of T cell ageing involve cell-intrinsic alterations and interactions with other immune and stromal cells. This study investigates how a tissue\'s microenvironment influences T cell ageing trajectories, following our discovery of varying rates of T cell ageing within a single host. Spleen-derived lymphocytes exhibited functional decline compared to those from lymph nodes, with proteomic analysis revealing increased expression of haem detoxification and iron storage proteins in aged spleen-derived lymphocytes. Exposure to the aged spleen microenvironment or to haem induced multiple ageing phenotypes in young lymphocytes, characterized by 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 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 ageing phenotypes in multiple solid organs of a young host. Our findings highlight the bidirectional relationship between T cells and their ageing microenvironment. Understanding these mechanisms will inform strategies to enhance immune responses in the elderly.