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- Title
Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response.
- Authors
Nevo, Shir; Frenkel, Noga; Kadouri, Noam; Gome, Tom; Rosenthal, Noa; Givony, Tal; Avin, Ayelet; Peligero Cruz, Cristina; Kedmi, Merav; Lindzen, Moshit; Ben Dor, Shifra; Damari, Golda; Porat, Ziv; Haffner-Krausz, Rebecca; Keren-Shaul, Hadas; Yarden, Yosef; Munitz, Ariel; Leshkowitz, Dena; Goldfarb, Yael; Abramson, Jakub
- Abstract
The thymus is a primary lymphoid organ that is essential for the establishment of adaptive immunity through generation of immunocompetent T cells. In response to various stress signals, the thymus undergoes acute but reversible involution. However, the mechanisms governing its recovery are incompletely understood. Here, we used a dexamethasone-induced acute thymic involution mouse model to investigate how thymic hematopoietic cells (excluding T cells) contribute to thymic regeneration. scRNA-seq analysis revealed marked transcriptional and cellular changes in various thymic populations and highlighted thymus-resident innate lymphoid cells type 2 (ILC2) as a key cell type involved in the response to damage. We identified that ILC2 are activated by the alarmins IL-25 and IL-33 produced in response to tissue damage by thymic tuft cells and fibroblasts, respectively. Moreover, using mouse models deficient in either tuft cells and/or IL-33, we found that these alarmins are required for effective thymus regeneration after dexamethasone-induced damage. We also demonstrate that upon their damage-dependent activation, thymic ILC2 produce several effector molecules linked to tissue regeneration, such as amphiregulin and IL-13, which in turn promote thymic epithelial cell differentiation. Collectively, our study elucidates a previously undescribed role for thymic tuft cells and fibroblasts in thymus regeneration through activation of the type 2 immune response. Editor's summary: The thymus undergoes transient but reversible involution in response to stress stimuli, but the molecular mechanisms mediating thymic regeneration after involution are not well defined. Nevo et al. performed scRNA-seq on the thymic non–T cell compartment after dexamethasone-induced acute thymic involution (ATI) in mice. Dexamethasone-induced ATI promoted a type 2 immune response driven by thymic resident ILC2s that were activated in response to tissue damage by IL-25 produced by thymic tuft cells and IL-33 produced by fibroblasts. ILC2s facilitated tissue regeneration by producing effector molecules including AREG, IL-13, CSF2, and IL-5, which promoted mTEC differentiation. Together, these findings identify a thymic tuft cell–fibroblast–ILC2 axis required for thymic regeneration after ATI. —Hannah Isles
- Subjects
REGENERATION (Biology); IMMUNE response; IMMUNOCOMPETENT cells; THYMUS; INNATE lymphoid cells; SKIN regeneration
- Publication
Science Immunology, 2024, Vol 9, Issue 91, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abq6930