ABSTRACT Targeting IL-18 in Thymic Regeneration The thymus, the organ responsible for T cell development, is both highly sensitive to acute injury and capable of regeneration. However, the thymus progressively loses its function with age such that there is markedly reduced capacity for T cell production and recovery from damage even early in adulthood. The thymus is particularly sensitive to pre-hematopoietic stem cell transplant (HCT) cytoreductive conditioning. Therefore, transplant recipients are at increased risk of opportunistic infection as well as relapse of malignancy during a prolonged period of T cell deficiency. No clinically approved strategies currently exist to improve thymic function and treat lymphopenia. Better understanding endogenous pathways of thymic damage and regeneration may inform therapeutic strategies to this end. Here, we provide evidence supporting the involvement of pyroptosis induced interleukin-18 (IL-18) as a negative regulator of thymopoieisis following acute injury and propose its targeting for improving organ function in settings of lymphopenia. Aim 1 of this study investigates the source of this suppressive IL-18 following acute damage by sublethal irradiation (SL-TBI) and its downstream cellular effectors. Specifically, we investigate thymic epithelial cells (TECs) and innate lymphoid cells within the thymus as effectors of IL-18’s mechanism of action. Aim 2 of this study proposes the temporal attenuation of IL-18 signaling using anti IL-18 monoclonal antibody as a novel therapeutic strategy to improve thymic recovery, and subsequently, peripheral T cell reconstitution and function. I put forward clinically relevant transplant models to assess its potential for improving regeneration post-HCT. Additionally, I will assess the potential of blocking IL-18 signaling in aged models of thymic involution. Together, these studies will not only provide insight into the biological mechanisms of tissue injury and repair, but also will offer an innovative therapeutic strategy to boost immune function especially in recipients of HCT.