Regenerating thymic T-cell production after bone marrow transplantation and during aging

Age-related thymic involution and the cytoablative treatments used for bone marrow transplantation cause severe damages on thymic epithelial cells, leading to impaired T-cell production, which increases susceptibility to cancers and infections and reduces vaccine efficacy. We identified the receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) axis as a key regulator of thymic recovery in these two pathophysiological contexts. Exogenous RANKL administration enhances thymic regeneration and T-cell production by promoting the recovery of thymic epithelial cell subsets and stimulating endothelial cells, which control the recruitment of circulating T-cell progenitors into the thymus. Notably, we demonstrated that RANKL treatment in aged mice rejuvenates the peripheral T-cell pool, resulting in improved antitumor and vaccine responses. Furthermore, RANKL stimulates both thymic epithelial and endothelial cells in human thymic organo-cultures. Collectively, these findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent an effective therapeutic strategy to enhance thymic regeneration, improve T-cell recovery after bone marrow transplantation, and counteract age-related immunosenescence.