Thymus engraftment and developmental progression of adoptively transferred progenitor T cells are affected by host...

Hematopoietic stem cell transplantation as treatment for patients with leukemia relies on chemotherapy and/or irradiation-based conditioning regimens to prevent graft rejection and cancer relapse. Despite advances in radiotherapy, total body irradiation for myeloablative conditioning is associated with dose and temporal heterogeneity, and how these variables impact thymus reconstitution and production of new T cells has not been fully elucidated. Here, we used in vitro-generated mouse progenitor T (proT) cells to investigate the dynamics of donor-derived cells in host thymuses under different irradiation regimens. Our results showed that proT cells are capable of homing to the thymus of both irradiated and nonirradiated mice. Notably, different irradiation protocols resulted in varying numbers of proT cells homing to the host thymus, revealing a critical time window for enhanced adoptive transfers of syngeneic and allogeneic donor cells. ProT cells given to mice, exposed to an optimal irradiation condition, showed enhanced thymus settling, slower developmental kinetics, and increased self-renewal capacity, when compared to suboptimal regimens. Our study provides valuable insights into the thymus-homing and cellular development mechanisms of transferred proT cells, as well as informing future therapeutic applications of in vitro-generated proT cells.