Triggered: How Damage Induced IL-18 Suppresses Thymus Regeneration
Year: 2024
Type: article
Abstract: The thymus is highly sensitive to acute injury such as the cytoreductive conditioning given pre-hematopoietic cell transplant (HCT). The thymus is capable of a remarkable degree of regeneration, however its reparative capacity and T cell productivity decline with age leaving HCT recipients vulnerable to relapse of malignancy and opportunistic infection. Better understanding endogenous mechanisms of thymus regeneration may inform therapeutic interventions to improve T cell reconstitution in these patients. Here, we report that HCT conditioning leads to rises in immunogenic cytokine IL-18, subsequent activation of NK cells and increased cytotoxicity, which suppresses organ recovery. We observe that HCT-conditioning by ionizing radiation leads to increased release of active of IL-18. We found that mice deficient for IL-18 (Il18r1−/−) exhibited increased thymic cellularity one week following acute damage by sublethal irradiation (SL-TBI) (Fig. 1A left). This led us to conclude that post-damage activation and release of IL-18 suppresses thymus regeneration. Within the thymus, IL-18R is expressed by highly radioresistant NK1.1+ NKT and NK cells. Depletion of both populations with anti-NK1.1 monoclonal antibody improved thymus cellularity in WT mice (Fig. 1A middle). Notably, NKT deficient CD1d−/− mice showed no defective repair which suggested that the depletion upon NK1.1+ cell depletion is largely mediated by NK cells. Depletion of NK1.1+ cells in Il18r1−/− mice did not improve regeneration further, suggesting that NK-mediated suppression is IL-18 dependent. Given the known role of IL-18 in NK cell activation, we hypothesized that the HCT-conditioning resultant rise in IL-18 stimulates NK cells leading to “accidental” targeting of regeneration promoting cells. NK cell production of cytotoxic factors including IFNg, GzmB and Perforin increases following radiation conditioning, although only mice deficient for Perforin and not IFNg exhibited improved thymus cellularity 7 days post HCT-conditioning (Fig 1A right). Further supporting this hypothesis, IL-18R+CD49b+ NK cells isolated from the thymus 2-days post-irradiation induced more target cell death in head-to-head cytotoxicity assays compared to NK cells isolated pre-radiation (Fig 1B). Finally, we observe TEC downregulation of NK cytotoxicity inhibitory ligand MHC-I following radiation conditioning, suggesting that critical regeneration promoting stroma may be the targets of these activated NK cells. These findings suggest that, while necessary for successful transplantation, conditioning regimens may induce cytotoxicity of bystander NK cells which suppresses thymus recovery. Furthermore, we implicate conditioning induced IL-18 in the stimulation of these suppressive cytotoxic cells and suggest that therapeutically targeting IL-18 and NK cell cytotoxicity may improve T cell reconstitution post-HCT.
Institution: Fred Hutch Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W4391604157