David Granadier, Kirsten Cooper, Dante Acenas II, Anastasia Kousa, Makya Warren, Vanessa Hernandez, Lorenzo Iovino, Paul deRoos, Emma E. Lederer, Steve Shannon-Sevillano, Sinéad Kinsella, Cindy Evandy, Marcel R. M. van den Brink, Andri Lemarquis, Jarrod A. Dudakov
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引用次数: 0
Abstract
Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4+ T cells, cytotoxic CD8+ T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects. The thymus is sensitive to acute insults including infection, as well as to injury from chemotherapy and myeloablative conditioning before hematopoietic cell transplantation. Here, Granadier et al. describe a role for IL-18 in limiting thymic regeneration by stimulating NK cells, which then target thymic epithelial cells.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.