2025/11/11 by Alice Machado, Chloé Houques, Marie Pouzolles +5 · 1 voice
Immunology and Microbiology · #IL-33, ST2, and ILC Pathways #T-cell and B-cell Immunology #Immune Cell Function and Interaction
paper · pdf · doi:10.1101/2025.11.10.687563
openalex publication_date 2025/11/11 · openalex created_date 2025/11/12 · openalex updated_date 2026/07/22
Abstract T cell deficiencies are commonly treated by intravenous hematopoietic stem/progenitor cell (HSPC) transplantation. However, this approach often leads to delayed and incomplete T cell reconstitution, partly due to impaired thymic function. In contrast, intrathymic delivery of HSPCs enables rapid, thymus-autonomous T cell development. Using a ZAP-70-deficient mouse model of severe immunodeficiency, we show that intrathymic transplantation of wild-type HSPCs results in robust thymic engraftment, with mature T cells and FOXP3+ regulatory T cells (Treg) detectable within four weeks. This reconstitution parallels the regeneration of a functional thymic medulla and the emergence of mature medullary thymic epithelial cells (mTECs). Importantly, we identify an early wave of donor-derived RORγT+ ILC3s that correlates with medullary regeneration. While dispensable for steady-state thymopoiesis, ILC3s accelerate medulla formation and support optimal T cell differentiation in this immunodeficient setting. These findings uncover a critical role for ILC3–TEC crosstalk in thymic repair and highlight intrathymic HSPC transplantation as a strategy to enhance immune reconstitution in immunodeficient hosts.