Interleukin 18 (IL-18) Suppresses Thymus Regeneration

Abstract The thymus is highly sensitive to acute injury, particularly to cytoreductive conditioning given pre-hematopoietic stem cell transplant (HCT). The thymus is capable of a remarkable degree 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 identify the inflammatory cytokine interleukin 18 (IL-18) as a suppressant of thymic function and propose its targeting to improve immune reconstitution. We posit that distinct forms of acute injury (i.e., irradiation, chemotherapy, infection and stress) lead to caspase-1 activation within the thymus and subsequently increased active IL-18. Our preliminary data suggests that IL-18 receptor (IL-18R) expressing natural killer (NK) cells are activated following acute damage in an IL-18 dependent fashion. Importantly, depletion of this NK1.1 +IL-18R +population improves thymus regeneration, suggesting that IL-18 induces an inflammatory response in organ-resident NK cells capable of impairing thymus repair. Our findings implicate IL-18 as a novel regulator of thymic regeneration and identify NK cells as likely mediators in its pathway. Furthermore, we suggest that IL-18 can be therapeutically targeted to improve T cell reconstitution following cytoreductive therapy and HCT. Supported by grants from NIH (R01 HL145276, P01 AG052359)