Intrasplenic Thymus Organogenesis from Injectable Tissue Fragments Restores Functional T‐Cell Immunity

Thymic hypofunction due to primary defects, aging, infection, or cytoreductive therapies causes profound restriction of the T-cell receptor (TCR) repertoire and increases rates of morbidity and mortality. Restoring thymic function is therefore critical. Here, the distinctive niche within the spleen has inspired the development of intrasplenic thymus regeneration (ISTR), an approach in which cultured thymic tissue fragments are implanted into the spleens of athymic nude mice, aged mice, thymectomized mice undergoing hematopoietic stem cell transplantation (HSCT), and humanized mice. The spleen's abundant vasculature and supportive stromal milieu enable rapid thymic organogenesis, leading to the reconstitution of phenotypically diverse and functional T-cell compartments, as well as protective responses to viral and tumor challenges. Relative to intramuscular implantation, ISTR drives faster and more complete thymic development, generates greater T-cell output, and is associated with a lower incidence of graft-vs.-host disease. In humanized animals, intrasplenic thymus grafts also promote the rapid emergence of functional human T cells. These results identify the spleen as an optimal ectopic niche for thymus regeneration and provide a promising strategy for clinical immune reconstitution and regenerative immunology.