The thymus is a small organ in which thymocytes generated in the bone marrow mature to become T cells of the adaptive immune system. Unfortunately, the thymus atrophies with age, its active tissue largely replaced by fat in most people by age 50 or so. Thereafter the adaptive immune system declines into immunosenescence and inflammaging, deprived of a sufficiently large supply of reinforcement cells. Given the importance of the immune system to health, in matters including tissue maintenance, resistance to infection, suppression of cancer, and more, regeneration of the thymus must be an important component of any serious effort to rejuvenate the elderly. Numerous approaches have been proposed, shown to work in mice, and some even attempted or demonstrated in humans, but this isn’t yet a solved problem.

One important class of approach to thymic regeneration is the delivery of cells that will home to the thymus. These cells can in principle be delivered via simple intravenous injection, rather than requiring a much more invasive introduction into the thymus directly. Once in the thymus they either directly assist in building new tissue, or deliver signals that encourage native stem cells to stop slacking and regenerate the thymus. An example of the type is the delivery of epithelial progenitor cells, demonstrated to produce thymic growth in mice a few years ago. Another example, as outlined in today’s open access paper, is to deliver cells that are somewhere in the lineage that starts with thymocytes and ends at T cells, as these will also home to the thymus, and their signaling encourages greater thymic activity. The cross-talk between hematopoietic cells in the bone marrow and the thymus is likely mediated by these cells and their signals.

Thymic Engraftment by in vitro-Derived Progenitor T Cells in Young and Aged Mice

T cells play a critical role in mediating antigen-specific and long-term immunity against viral and bacterial pathogens, and their development relies on the highly specialized thymic microenvironment. T cell immunodeficiency can be acquired in the form of inborn errors, or can result from perturbations to the thymus due to aging or irradiation/chemotherapy required for cancer treatment. Hematopoietic stem cell (HSC) transplant (HSCT) from compatible donors is a cornerstone for the treatment of hematological malignancies and immunodeficiency. Although it can restore a functional immune system, profound impairments exist in recovery of the T cell compartment. T cells remain absent or low in number for many months after HSCT, depending on a variety of factors including the age of the recipient.

While younger patients have a shorter refractory period, the prolonged T cell recovery observed in older patients can lead to a higher risk of opportunistic infections and increased predisposition to relapse. Thus, strategies for enhancing T cell recovery in aged individuals are needed to counter thymic damage induced by radiation and chemotherapy toxicities, in addition to naturally occurring age-related thymic involution.

Preclinical results have shown that robust and rapid long-term thymic reconstitution can be achieved when progenitor T cells, generated in vitro from HSCs, are co-administered during HSCT. Progenitor T cells appear to rely on lymphostromal crosstalk via receptor activator of NF-κB (RANK) and RANK-ligand (RANKL) interactions, creating chemokine-rich niches within the cortex and medulla that likely favor the recruitment of bone marrow-derived thymus seeding progenitors. Here, we employed preclinical mouse models to demonstrate that in vitro-generated progenitor T cells can effectively engraft involuted aged thymuses, which could potentially improve T cell recovery. The utility of progenitor T cells for aged recipients positions them as a promising cellular therapy for immune recovery and intrathymic repair following irradiation and chemotherapy, even in a post-involution thymus.