TY - JOUR
T1 - Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response
AU - Nevo, Shir
AU - Frenkel, Noga
AU - Kadouri, Noam
AU - Gome, Tom
AU - Rosenthal, Noa
AU - Givony, Tal
AU - Avin, Ayelet
AU - Cruz, Cristina Peligero
AU - Kedmi, Merav
AU - Lindzen, Moshit
AU - Dor, Shifra Ben
AU - Damari, Golda
AU - Porat, Ziv
AU - Haffner-Krausz, Rebecca
AU - Keren-Shaul, Hadas
AU - Yarden, Yosef
AU - Munitz, Ariel
AU - Leshkowitz, Dena
AU - Goldfarb, Yael
AU - Abramson, Jakub
N1 - Publisher Copyright: © 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85182299694&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciimmunol.abq6930
DO - https://doi.org/10.1126/sciimmunol.abq6930
M3 - مقالة
C2 - 38215193
SN - 2470-9468
VL - 9
JO - Science Immunology
JF - Science Immunology
IS - 91
M1 - eabq6930
ER -