T cells are incredible. They detect foreign or abnormal proteins with remarkable specificity. Some directly kill cells containing these proteins while others call to additional components of the immune system for help in fighting the unwelcome invaders. They are a vital component of a functional immune system.
These potent, highly specific cells don’t just come out of nowhere – T cell development is a complex and tightly regulated process. The bulk of this process occurs in the thymus, an organ located just behind the sternum in the chest that functions as a T cell training center. In the thymus, T cell precursors develop their target specificity, mature cell killing or helper function, and undergo a series of tests. Most T cells, including those that recognize normal human proteins, are weeded out in the process. Only the best of the best – the pathogen and aberrant protein fighters – are released to patrol the body.
The thymus is not immune to damage. Infections and high levels of stress hormones can impact its function. Some cancer therapies, including hematopoietic cell transplantation and chemotherapy, injure the thymus and deplete other immune cell populations. When the thymus is damaged, T cell production halts. Prolonged thymus recovery increases susceptibility to infections and malignancies. Developing therapies that speed up thymus regeneration could mitigate this susceptibility.
Finding ways to accelerate thymus recovery first requires understanding how the thymus responds to acute injury. In a recent study published in Nature Immunology, researchers from the Dudakov lab in the Translational Science and Therapeutics Division identified a new regulatory pathway in thymus regeneration.
The team used mouse models to look at thymus recovery to several types of injury – hematopoietic cell transplant conditioning, chemotherapy, stress hormones, and bacterial infection. They found that all types of thymus damage led to an increase in levels of the pro-inflammatory signaling molecule IL-18. Administering additional IL-18 to mice delayed thymus recovery while blocking IL-18 signaling improved regeneration. This suggested that IL-18 signaling inhibits healing. But how?
Like other signaling molecules, IL-18 binds to a specific receptor, IL-18R, on the surface of target cells. The interaction between the signaling molecule and the receptor triggers a change in cell function. The team uncovered the signaling pathway by first identifying the IL-18 target cells. They measured cell surface protein expression of IL-18R across cell types in the thymus and found that Natural Killer (NK) cells have the highest expression of the receptor.
NK cells target and kill cells that have unusual surface protein expression profiles, common in viral infection or cancer. They are a central component of the fast-acting innate immune system. The study authors observed that depleting NK cells in their model mice improved thymus regeneration, implicating this cell type in impairing recovery. The study further revealed that in the injured thymus, IL-18 signaling leads to NK cell activation. In response to IL-18, these cells increase expression of perforin, a molecular weapon they use to perforate (and kill) targeted cells.
Additionally, the researchers found that thymus epithelial cells, which play a crucial role in T cell development, also change protein expression in response to thymus damage. The cells decrease MHC-1 and increase Rae1 expressed on their cell surface – both changes that are characteristic of unhealthy cells and targets for NK cell cytotoxicity. Indeed, the researchers found that activated NK cells kill thymus epithelial cells from damaged thymuses.
In all, thymus damage releases IL-18, which activates NK cells to kill remaining thymus epithelial cells. Damage results in more damage, which slows down the process of rebuilding and recovering.
Encouragingly, this pathway could be targeted to accelerate thymus recovery. David Granadier, a graduate student in the lab and lead author on the study, commented, “blocking the activity of IL-18 or cytotoxic NK cells could be harnessed to improve thymus function and T cell reconstitution in patients who receive hematopoietic cell transplantation or chemotherapy.” The next question, Granadier says, is “whether doing so may affect graft-versus-leukemia activity or susceptibility to opportunistic infection."
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Lorenzo Iovino and Jarrod Dudakov contributed to this research.
The spotlighted research was funded by the National Institutes of Health.
Granadier D, Cooper K, Acenas D, Kousa A, Warren M, Hernandes V, Iovino L, deRoos P, Lederer EE, Shannon-Sevillano S, Kinsella S, Evandy C, van den Brink MRM, Lemarquis A, Dudakov JA. 2025. Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration. Nature Immunology. doi: 10.1038/s41590-025-02270-z
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.
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