Mesenchymal stromal cells counteract with age-related immune decline and enhance vaccine efficacy by modulating endogenous splenic marginal reticular cells in elderly models.

Vaccination is the preferred strategy for preventing infections such as influenza in elderly individuals; however, its efficacy is often suboptimal due in part to age-related declines in immune function. In this study, we discovered that the infusion of mesenchymal stromal cells (MSCs) restored defects in the splenic stromal cell network and lymphocyte architecture in aged mice while also increasing specific antibody levels following vaccine immunization. This significantly protected aging mice from influenza infection. Mechanistically, the delivered MSCs localized in the splenic marginal zones, where they positioned themselves near marginal reticular cells (MRCs) and stimulated MRC proliferation, partially through the action of vascular endothelial growth factor A (VEGFA). This MSC‒MRC interaction orchestrated the reconstruction of the stromal network, thereby restoring lymphocyte homeostasis and germinal center reactions. Importantly, the MSC-mediated enhancement of the vaccine response was further validated in aged cynomolgus monkeys. Collectively, our findings provide new insights into the application of MSCs in addressing age-related immune decline and highlight splenic MRCs as critical therapeutic targets.