Enhancing thymic function improves T-cell reconstitution and immune responses in aged mice

Age-related thymic involution leads to diminished output of naïve T-cells. While this process is suggested to increase the risk of disease severity in the elderly following infection, direct evidence is lacking. We developed two mouse models that allow us to experimentally prevent or reverse thymic involution. Constitutive Myc expression in thymic epithelial cells (TEC) of middle-aged mice enhanced thymic function, and increased numbers of peripheral naïve CD4 and CD8 T-cells. Inducible Myc expression reversed age-related thymic involution and partially recovered peripheral naïve T-cell numbers. Importantly, improving thymic function in these settings preserved T-cell-dependent antibody responses and significantly reduced T-cell-associated mortality after infection with Toxoplasma gondii. Improved thymic function also rebalanced age-associated alterations in the Treg pool, and mitigated loss of the transcriptional Th1 signature in aged conventional T-cells. Our findings support the value of TEC-focused thymic regeneration strategies for enhancement of T-cell-mediated immunity in the elderly.