Controlling thymus function to improve T-cell immunity in the aged.

Effective adaptive immunity is dependent on T-cell development in the thymus. The thymus undergoes age-related involution, leading to reduced T-cell output. This is suggested to compromise T-cell immunity and increase risk of disease severity in the elderly. However, it was unknown whether enhancing thymic function would ameliorate the immune defects observed in the elderly. Transcriptional assessment of thymic epithelial cells (TECs) through development facilitated the generation of genetically altered mouse models in which thymic involution was prevented or reversed. Both models restored normal peripheral T cell populations, and, critically, enhanced the survival of aging hosts when challenged with Toxoplasma gondii. Therefore, TEC-mediated restoration of thymic function improves immunity with age. Based on these findings, I propose to identify progenitor-successor relationships within adult TECs that maintain the adult thymus and identify age-associated alterations in these populations that could contribute to thymic atrophy. Moreover, I will investigate the mechanisms by which restored thymus function improves immunity in aged mice. Collectively, my proposal will provide an important understanding of how TECs shape immune responses in the elderly, and inform TEC-mediated approaches of thymic regeneration to aid prevention of the degeneration of T-cell immunity that accompanies aging.