{"doi":"10.1101/2025.11.10.687563","title":"Intrathymic progenitor cell transplantation restores T cell development through ILC3-TEC crosstalk","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":581238,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1492893,"name":"Chloé Houques","orcid":null,"position":1,"is_corresponding":false},{"id":518156,"name":"Marie Pouzolles","orcid":"0000-0003-1808-820X","position":2,"is_corresponding":false},{"id":1492894,"name":"Elisa Evain","orcid":null,"position":3,"is_corresponding":false},{"id":632975,"name":"Valérie Dardalhon","orcid":"0000-0003-0533-2920","position":4,"is_corresponding":false},{"id":471416,"name":"Christelle Harly","orcid":"0000-0002-8045-9166","position":5,"is_corresponding":false},{"id":113313,"name":"Naomi Taylor","orcid":"0000-0002-2459-4558","position":6,"is_corresponding":false},{"id":310095,"name":"Valérie S. Zimmermann","orcid":null,"position":7,"is_corresponding":false},{"id":518774,"name":"Alice Machado","orcid":null,"position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:58:47.357782Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}