Fig. 2

Replacement, reprogramming, and restoration strategies for reconstitution of senescent and exhausted cells in T cell pool. (1) Replacement: targeting of directed apoptosis in senescent cells as shown by Baar et al. and rebuilding the T cell pool by ASCT. Top left: blockage of P53/FOXO4 binding in fibroblasts using a bioengineered FOXO4-DRI peptide. Top right: collection, purification, and expansion of hematopoietic stem cells, followed by cryopreservation and reinfusion into patient after chemotherapy. (2) Reprogramming: isolation of senescent and exhausted antigen-specific T cells followed by reprogramming into IPSCs, expansion, induction of T cell lineage, and transduction of engineered CAR and TCR before injection. (3) Restoration: preparation of a functional thymus organoid by thymectomy of cadaveric donor, isolation of TEM, transduction with recipient MHC, and recellularization of bioengineered organoid scaffold before transplantation into recipient