Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response
Shir Nevo, N Frenkeĺ, Noam Kadouri, Tom Gome, Noa Rosenthal, Tal Givony, Ayelet Avin, Cristina Peligero Cruz, Merav Kedmi, Moshit Lindzen, Shifra Ben‐Dor, Golda Damari, Ziv Porat, Rebecca Haffner‐Krausz, Hadas Keren‐Shaul, Yosef Yarden, Ariel Munitz, Dena Leshkowitz, Yael Goldfarb, Jakub Abramson
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.