Inducible thymic epithelial cell-based rejuvenation in thymic aging-associated inflammaging (Supported by NIH/NIAID R01AI121147)

Abstract

Abstract Age-related thymic involution primarily results from a decline in the transcription factor forkhead box N1 (FOXN1), while input of exogenous FOXN1 is able to significantly rescue thymic aging. Given that FOXN1 over-expressing fibroblasts (inducible thymic epithelial cells, iTECs) can generate an ectopic de novo thymus and engrafted young TECs can lead to middle-aged thymus regrowth, we asked whether engrafting iTECs directly into the aged thymus and perithymus can be a strategy to rescue aged thymic function. The re-establishment of central tolerance is crucial to attenuate age-associated chronic inflammation in the elderly (termed inflammaging). This will reduce increased self(auto)-reactivity, an important contributor to inflammaging. Intrathymic transplantation of iTECs into the aged murine thymus revealed that iTECs drove partial regrowth of the aged thymus, equally well in both male and female mice. The iTECs also rejuvenated aged thymic architecture, including regeneration of well-organized thymic medulla, and improvement of aged thymic function, including re-enforcement of thymocyte negative selection-related Aire gene expression. This led to reduction of self-reactivity-resulted inflammaging, including pro-inflammatory cytokines (IL-6 and IL-1b) and lymphoinfiltration to non-lymphoid organs, in old mice. Our findings support this potential novel strategy for enforcing the declined thymocyte negative selection to partially restore central tolerance in the elderly and reduce inflammaging.