Regulation of thymic regeneration by GPR39

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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). In our preliminary data we have shown that Zinc (Zn), which is the second most abundant transition metal in the body, is critically important for T cell development; with mice fed a Zn-deficient diet exhibiting a profound block in the differentiation and expansion of thymocytes, which was reversed with dietary supplementation of Zn in drinking water. Although Zn, which is a co-factor for over 300 proteins and has been implicated in cell processes such as proliferation and apoptosis, directly influences T cell development at the level of thymocytes, we found an increase in the levels of extracellular Zn after damage; and that this translocation of Zn could directly stimulate the damage-associated production of BMP4 by ECs via sensing of Zn by the G- protein-coupled receptor GPR39.m These studies suggest that under steady-state conditions Zn is used to promote T cell development, but after damage, Zn released by thymocytes is capable of triggering the regenerative response by ECs by stimulating GPR39, effectively acting as a damage-associated molecular pattern (DAMP). Based on our preliminary data, we hypothesize that (a) a switch toward immunogenic cell death (ICD) in thymocytes after damage leads to the extracellular release of Zn; (b) GPR39-sensing of released zinc is a master regulator of the endogenous regenerative response to acute damage; and (c) activation of GPR39 signaling can be exploited into a superior method to promote thymic function and T cell reconstitution following HSCT. Specifically, our proposal has the following aims: (1) to investigate the ability of GPR39 signaling to induce multiple distinct pathways of endogenous regeneration after damage; (2) to identify the role of thymocyte cell death in initiating the production of regenerative factors; and (3) to evaluate if modulation of GPR39 signaling can be used as a means of improving T cell reconstitution following HSCT. 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.