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bioRxiv · 10.1101/2025.11.10.687563

Intrathymic progenitor cell transplantation restores T cell development through ILC3-TEC crosstalk

Machado, A.·Houques, C.·Pouzolles, M.·Evain, E.·Dardalhon, V.·Harly, C.·Taylor, N.·Zimmermann, V. S.
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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 ROR{gamma}T+ 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.

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Machado, A., Houques, C., Pouzolles, M., Evain, E., Dardalhon, V., Harly, C., Taylor, N., Zimmermann, V. S.. 2025-11-11. Intrathymic progenitor cell transplantation restores T cell development through ILC3-TEC crosstalk. https://doi.org/10.1101/2025.11.10.687563

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