Hematopoietic Stem Cell Transplantation (HCT) Conditioning Leads to NK Cell Cytotoxicity Limiting Endogenous Thymus Regeneration

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.461-461
• Main Authors: Granadier, David, Cooper, Kirsten, Acenas II, Dante Dennis, Iovino, Lorenzo, Deroos, Paul, Hernandez, Vanessa A, Dudakov, Jarrod A
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-188387

The thymus is highly sensitive to acute injury such as the cytoreductive conditioning given pre-hematopoietic stem cell transplant (HCT). The thymus is capable of regeneration, however its reparative capacity and T cell productivity decline with age. This leaves HCT recipients vulnerable to relapse of malignancy and opportunistic infection - the leading causes of post-HCT mortality - during a prolonged period of lymphopenia. Better understanding the endogenous mechanisms by which thymus regeneration is regulated may inform therapeutic interventions to improve T cell reconstitution in these patients. Here, we report that HCT conditioning leads to rises in stimulatory cytokine IL-18, subsequent activation of NK cells and increased cytotoxicity, which aberrantly suppresses organ recovery. Our group has reported that HCT-conditioning by ionizing radiation leads to increased Caspase-1 mediated immunogenic cell death within the thymus (Kinsella 2023 BioRxiv). Consistent with the cleavage of Caspase-1, we found an increase in release of the inflammatory cytokines IL-1b and IL-18. Although mice deficient for IL-1b signaling receptor ( Il1r -/-) did not show any modulation in their ability to regenerate after TBI, we found that mice deficient for IL-18 signaling (Il18 -/-) 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. We found that IL-18R was not expressed on most developing thymocytes and although a minority of thymic epithelial cells expressed the receptor, mice with a deficiency in IL-18R restricted to TECs ( Il18r1fl/fl:Foxn1-Cre +) showed no difference in regenerative capacity following conditioning. To rule out an effect on hematopoietic progenitors, for which IL-18R expression has been reported ( Silberstein 2016 Cell Stem Cell 6;19), we performed a competitive transplantation of Il18r1 -/- and WT bone marrow and measured T cell production, which showed no competitive advantage of Il18r1 -/- donor cells; this demonstrated that IL-18 does not directly regulate progenitor cells themselves, but rather, more likely acts via a bystander thymus-resident population. Within the thymus, IL-18R was 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