Session: 703. Cellular Immunotherapies: Basic and Translational III
Hematology Disease Topics & Pathways:
Biological therapies, Fundamental Science, Research, Translational Research, Immune Disorders, Diseases, immunodeficiency, Therapies, Transplantation
Recently, our group reported that attenuation of homeostatic detection of apoptotic thymocytes after damage regulates tissue regeneration by releasing the brakes on the production of the regenerative factors IL-23 and BMP4 (Kinsella 2021 Cell Rep 37:1). However, our preliminary data also shows that upon acute damage by ionizing radiation, there is a switch towards an immunogenic pyroptotic cell death with an increase in cleaved caspase 1 (pyroptotic caspase) and release of damage-associated molecular patterns. Among these was the release of the caspase 1 dependent inflammatory factors IL-1b and IL-18 within the thymus following damage. Although mice deficient for IL-1b receptor (Il1r-/-) did not show any modulation in their ability to regenerate after total body irradiation (TBI), we found that mice deficient for IL-18 (Il18-/-) exhibited increased thymic cellularity (Fig. 1A). Based on these findings, we hypothesized that immunogenic cell death-induced IL-18 suppresses thymic repair following acute insult and that IL-18 can be targeted to improve T cell reconstitution in settings of lymphopenia.
Although IL-18R was expressed by a substantial fraction of medullary thymic epithelial cells (mTECs), and TECs serve as the master regulators of thymic function, mice with a deletion for IL-18R specifically in TECs (using Il18r1fl/flFoxn1Cre+ mice) did not show any altered regenerative capacity compared to control mice, suggesting that IL-18 does not act directly on TECs. Instead, we determined most IL-18R expression was restricted to NK1.1+ Innate Lymphoid Cells. Strikingly, in vivo depletion of this population prior to induction of damage significantly improved thymic regeneration (Fig. 1B), consistent with what we observed in IL-18 deficient mice. Importantly, we found that thymic NK cells were activated after damage, with increased expression of Perforin, Gzma, and Gzmb, as well as the activation markers Nkg7, Klrd1, and Klrk1 (NKG2D). Suggestive of a mechanism that could be mediating this, mice with a germline deletion for Perforin showed improved thymus repair following acute damage further supporting an NK cell mediated mechanism of thymic suppression. Finally, mice treated with an antibody against IL-18 demonstrated early signs of improved thymic regeneration and export of new naïve T cells in a mouse model of allogeneic HCT.
Taken together, these findings implicate the inflammatory cytokine IL-18, signaling through NK cells, as suppressive to endogenous thymic regeneration. Furthermore, our data suggests that this pathway can be therapeutically targeted to improve T cell reconstitution following cytoreductive therapy and HCT.
Disclosures: No relevant conflicts of interest to declare.
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