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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.<\/jats:p>","DOI":"10.1126\/sciimmunol.abq6930","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T18:58:21Z","timestamp":1705085901000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":42,"title":["Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6913-1867","authenticated-orcid":true,"given":"Shir","family":"Nevo","sequence":"first","affiliation":[{"name":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, 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