Friday, May 9, 2025
5/9/2025
Promoting T cell reconstitution after hematopoietic cell transplantation - PROJECT SUMMARY The thymus, which is the primary site of T cell generation, is extremely sensitive to injury; but also has a remarkable capacity for endogenous repair. However, even though there is continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage caused by common cancer therapies and the conditioning regimes for hematopoietic cell transplantation (HSCT) lead to prolonged T cell lymphopenia. Furthermore, in the context of allogeneic HCT, the thymus is an extremely sensitive target to alloreactive T cells during graft versus host disease (GVHD). Consequently, identification of therapies that can boost T cell reconstitution in recipients of HSCT is a clinical priority. We have previously identified two distinct pathways of endogenous thymic regeneration, centered on the production of the regeneration factors IL-22 by innate lymphoid cells (ILCs), and BMP4 by endothelial cells (ECs); both of which mediate their regenerative effects by targeting thymic epithelial cells (TECs). More recently we have found that the trigger for these distinct regenerative pathways hinge on the balance between forms of cell death, with immunologically silent apoptosis (which is abundant in thymocytes during steady-state) suppressive to the regenerative program. On the other hand, after thymic damage caused by radiation injury, we found a switch toward immunogenic cell death, with the resulting release of damage-associated molecular patterns (DAMPs) sufficient to promote regeneration. Specifically, we identified that intracellular Zn was released after radiation injury, where it could signal through the G-protein coupled receptor 39 (GPR39) to stimulate production of BMP4 and IL-23, a key upstream regulator of IL-22 production. Separately, we also found that the release of the prototypical DAMP, ATP, was able to signal directly on thymic epithelial cells through purinergic (P2) receptors and promote their expression of Foxn1, key microenvironmental drivers of T cell development. Importantly, our preliminary data also suggests that each of these pathways can be therapeutically targeted to improve thymic recovery in mouse models of HCT. Our preliminary data has also identified putative TEC precursors that are important for regenerating the epithelial compartment and thus promoting regeneration, as well as the emergence with age of aberrant epithelial cells that limit thymic function, including in its reparative capacity after acute damage. Our research program is thus exploring several key questions: What are the triggers and upstream regulators of endogenous tissue regeneration in the thymus? Which cells mediate tissue regeneration in the thymus after acute injury? Are there limitations to endogenous regeneration after HCT across sex and lifespan? Can we exploit these mechanisms of endogenous regeneration to develop therapeutic strategies to boost T cell reconstitution in HCT recipients? The studies outlined in this proposal not only have the potential to define important pathways underlying tissue regeneration but could also result in innovative clinical approaches to enhance thymic function.
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