Uncovering Mechanisms Regulating Thymus Regeneration: Damage Induced Interleukin-18 Triggers NK Cells to Suppress Thymus Repair

Abstract

The thymus is the primary lymphoid organ responsible for T cell production. While the thymus is highly sensitive to acute stressors, in particular, treatments for malignancy such as chemotherapies and the myeloablative conditioning received pre-hematopoietic cell transplantation (HCT), it also has a tremendous capacity for regeneration following acute damages. However, the organ declines in its T cell production and reparative capacity with age in a natural process known as age-related thymus involution. This leaves patients experiencing thymus damage, particularly HCT-recipients, vulnerable to leading causes or post-transplant mortality (relapse of primary malignancy, graft-versus-host disease and opportunistic infection) during a prolonged period of T cell lymphopenia. Though the phenomeneon of endogenous thymus regeneration following its injury was known even before the organ’s immunological function was understood, the mechanisms underpinning it remain incompletely understood. Recent works have begun to uncover these regenerative mechanisms. Yet, there remains no clinically approved treatment for T cell lymphopenia following thymus damage. In this dissertation, I identify a novel pathway regulating thymus recovery following acute injury in which damage-induced Interleukin-18 (IL-18) suppresses regenerative processes via the activation of organ-resident cytotoxic natural killer (NK) cells. We show that several different models of acute damage led to an acute rise in the cleavage of Caspase-1 which mediates an immunogenic form of cell death known as pyroptosis during which mature IL-18 and IL-1 are released from dying cells. While IL-1 had no effect on thymus recovery, mice deficient in IL-18 signaling showed improved thymus reconstitution and pharmacologic abrogation of IL-18 improved thymus reconstitution in clinically relevant modeling of hematopoietic cell transplantation. We identify organ resident dendritic cells (DCs) and rare stromal populations including capsular fibroblasts and mesothelial cells as sources of functional IL-18 following injury. Our studies demonstrate that IL-18 mediates its effects via the stimulation of damage-resistant cytotoxic NK cells that suppress thymic recovery by targeting thymic epithelial cells (TECs), which serve as master regulators of organ function and regeneration. Finally, we show that injury induced genotoxic stress in TECs, and particularly medullary TECs (mTECs), results in their increased vulnerability to NK cytotoxicity via the downregulation of NKG2D inhibitory ligand MHC-I and upregulation of NKG2D stimulatory ligand Rae-1.