Thymic epithelial cell loss results in age-related thymic involution and immune deficiency. We investigated mechanisms of TEC loss during chronological aging (6 weeks, 7 months, 15 months) of normal C57BL6/J mice. Aged TEC showed replicative senescence with increased apoptosis, decreased proliferation, decreased telomerase activity and shortened telomere length. A subpopulation of aged TEC expressed Fas in response to pro-inflammatory cytokines (TNFα,IL-1β) made by aged thymocytes. Fas signaling and caspase-8 activation were induced by FasL selectively expressed by aged intrathymic memory T cells. Combined pharmacological inhibition of Caspase-8 and TEC growth stimulation by KGF restored thymopoiesis to neonatal levels. Aged TEC differentially expressed a 175-gene set predicted to be dually regulated by two transcription factors, NF-κB and HNF4α, which are activated by inflammatory cytokines and fatty acids, respectively. NF-κB and HNF4α signaling in aged TEC was confirmed by ChIP assays demonstrating binding to promoters of age-related genes, gene reporter assays, and synergistic induction of TEC apoptosis by inflammatory cytokines and fatty acids. TEC aging is mediated by the convergence of different TFs responsive to inflammatory and metabolic signals on shared promoters. Thymic regeneration in aging will require mitigation of the effects of non-autonomous inflammatory and metabolic signals, e.g., from infection and obesity, which drive TEC death and thymic involution.

2014