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Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration
David Granadier1,2, Kirsten Cooper3, Dante Acenas3,4
1Translational Science and Therapeutic Division and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA. dgranadi@fredhutch.org.
Nature Immunology
|September 11, 2025
Summary
Interleukin-18 (IL-18) released after tissue damage impairs thymus regeneration by activating natural killer (NK) cells. Targeting IL-18 may enhance immune recovery and offer insights into cancer immunotherapy side effects.
Area of Science:
- Immunology
- Cell Biology
- Regenerative Medicine
Background:
- Interleukin-18 (IL-18) is a pro-inflammatory cytokine vital for antiviral immunity.
- IL-18 activates T helper 1 CD4+ T cells, cytotoxic CD8+ T cells, and natural killer (NK) cells.
- Thymic regeneration is essential for restoring immune competence after insults like stress, infection, or chemotherapy.
Purpose of the Study:
- To investigate the role of IL-18 in thymic regeneration following tissue damage.
- To elucidate the mechanism by which IL-18 affects thymic recovery.
- To explore IL-18 as a potential therapeutic target for boosting thymic function.
Main Methods:
- Analysis of mature IL-18 generation in the thymus after various forms of tissue damage.
- Investigation of caspase-1-mediated immunogenic cell death pathways.
- Assessment of IL-18-stimulated NK cell activity and their impact on thymic epithelial cells.
Main Results:
- Mature IL-18 is generated in the thymus following tissue damage via caspase-1-mediated cell death.
- IL-18-stimulated NK cells inhibit endogenous thymic regeneration.
- NK cells target thymic epithelial cells, disrupting thymus recovery and immune competence restoration.
Conclusions:
- A novel pathway regulating thymic regeneration involving IL-18 and NK cells has been identified.
- IL-18 inhibition could be a therapeutic strategy to promote thymic function and immune recovery.
- Findings provide insights into potential off-target effects of IL-18 in cancer immunotherapy.
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