Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable capacity for endogenous repair. Although there is continual thymic involution and regeneration in response to everyday insults like stress and infection, acute and profound thymic damage caused by common cancer therapies and the conditioning regimes used as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines further as a function of age. We have previously identified two independent pathways of endogenous thymic regeneration, centered on the production of the regeneration-associated factors (RAFs) 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. Although we and others have previously identified dendritic cell (DC)-produced IL-23 as critical for controlling the production of IL-22 by ILCs, the underlying mechanisms that trigger the regenerative response via the production of these distinct RAFs is poorly understood. In our preliminary data we have demonstrated that deletion of the pattern recognition receptor NOD2 results in a significant increase in the production of IL- 22, IL-23, and BMP4, leading to improved thymus recovery after damage caused by total body irradiation. This suggests that under steady-state conditions, NOD2 signaling suppresses the production of these regenerative cytokines; but after damage this negative stimulus is removed, thereby enabling tissue repair by activating the production of RAFs. Based on these findings, we hypothesize that (a) intrinsic NOD2 signaling in DCs and ECs suppresses the production of IL-23 and BMP4, respectively; (b) NOD2-mediated suppression of RAFs is abolished after damage by the depletion of thymocytes; and (c) that this common pathway of regeneration can be exploited into a superior method to promote thymic function following HCT. Specifically, our proposal has the following aims: (1) To investigate the role of NOD2 in regulating endogenous thymic regeneration after acute damage; (2) To identify the regulators of NOD2 signaling that suppress the steady-state production of RAFs; and (3) To study if these pathways can be modulated as a means of improving T cell reconstitution following HCT. The mechanistic and pre-clinical studies outlined in this proposal not only have the potential to define important novel pathways underlying tissue regeneration, but could also result in innovative clinical approaches to enhance T cell reconstitution in recipients of HCT, as well as patients whose thymus has been decimated due to age, infection or other cytoreductive cancer therapies.
Endogenous thymic regeneration is a crucial process that enables restoration of immune competence after damage caused by everyday insults like stress and infection. However, this regenerative capacity diminishes with age, and after severe injury such as that caused by chemotherapy and the conditioning required for successful hematopoietic cell transplant (HCT), contributes to a prolonged period of immune depletion. In this proposal we seek to understand the common mechanisms that govern regenerative responses in the thymus so that they may be exploited into rational therapeutic strategies to boost immune function in recipients of HCT, as well as patients whose thymus has been decimated due to age, infection or common cancer treatments.