{"doi":"10.1038/s41590-024-01915-9","title":"Age-related epithelial defects limit thymic function and regeneration","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.</jats:p>","journal":"Nature Immunology","year":2024,"id":617887,"datarank":0.6610078870896381,"base_score":4.406719247264253,"endowment":4.406719247264253,"self_citation_contribution":0.6610078870896381,"citation_network_contribution":0.0,"self_endowment_contribution":0.6610078870896381,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":81,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":841671,"name":"Lorenz Jahn","orcid":"0000-0002-9880-7026","position":1,"is_corresponding":false},{"id":1593640,"name":"Kelin Zhao","orcid":null,"position":2,"is_corresponding":false},{"id":1593641,"name":"Angel E. Flores","orcid":null,"position":3,"is_corresponding":false},{"id":235401,"name":"Dante Acenas","orcid":"0000-0003-4137-0297","position":4,"is_corresponding":false},{"id":639173,"name":"Emma Lederer","orcid":"0009-0008-4103-5388","position":5,"is_corresponding":false},{"id":246045,"name":"Kimon V. Argyropoulos","orcid":"0000-0003-1510-5887","position":6,"is_corresponding":false},{"id":1593642,"name":"Andri L. Lemarquis","orcid":null,"position":7,"is_corresponding":false},{"id":567723,"name":"David Granadier","orcid":"0000-0002-1983-4190","position":8,"is_corresponding":false},{"id":567720,"name":"Kirsten Cooper","orcid":"0000-0002-0711-2713","position":9,"is_corresponding":false},{"id":1593643,"name":"Michael D’Andrea","orcid":"0000-0002-2557-3628","position":10,"is_corresponding":false},{"id":285407,"name":"Julie M. Sheridan","orcid":"0000-0002-1478-3662","position":11,"is_corresponding":false},{"id":345073,"name":"Jennifer J. 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Wimmer","orcid":"0000-0002-9931-8179","position":26,"is_corresponding":false},{"id":857839,"name":"Kelly L. Rogers","orcid":"0000-0002-6755-0221","position":27,"is_corresponding":false},{"id":268582,"name":"Susan DeWolf","orcid":"0000-0002-2754-3537","position":28,"is_corresponding":false},{"id":1051874,"name":"Brianna Gipson","orcid":"0009-0005-5837-8676","position":29,"is_corresponding":false},{"id":108833,"name":"Antonio L. C. Gomes","orcid":"0000-0003-3790-3724","position":30,"is_corresponding":false},{"id":2917,"name":"Manu Setty","orcid":"0000-0002-0344-2627","position":31,"is_corresponding":false},{"id":104368,"name":"Dana Pe’er","orcid":"0000-0002-9259-8817","position":32,"is_corresponding":false},{"id":1593654,"name":"Laura Hale","orcid":null,"position":33,"is_corresponding":false},{"id":488525,"name":"Nancy R. Manley","orcid":"0000-0001-8489-7764","position":34,"is_corresponding":false},{"id":95279,"name":"Daniel H.D. Gray","orcid":"0000-0002-8457-8242","position":35,"is_corresponding":false},{"id":108880,"name":"Marcel R.M. van den Brink","orcid":"0000-0003-0696-4401","position":36,"is_corresponding":false},{"id":299076,"name":"Jarrod A. Dudakov","orcid":"0000-0001-6220-5632","position":37,"is_corresponding":false},{"id":661695,"name":"Anastasia I. Kousa","orcid":"0000-0002-4550-0389","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Age-related epithelial defects limit thymic function and regeneration.","abstract":"The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39112630","pmcid":"PMC11362016","openalex_id":null,"authors":[],"funders":[{"funder_name":"Department of Health | National Health and Medical Research Council (NHMRC)","grant_id":"1078763","title":"The cell death mechanisms that control regulatory T cell homeostasis"},{"funder_name":"Department of Health | National Health and Medical Research Council (NHMRC)","grant_id":"1187367","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL123340","title":null},{"funder_name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)","grant_id":"R01-CA228308","title":null},{"funder_name":"U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)","grant_id":"R01-HL145276","title":null},{"funder_name":"U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)","grant_id":"R01-HL165673","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R35 HL171556","title":null},{"funder_name":"Cancer Council Victoria","grant_id":"1102104","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA015704","title":null},{"funder_name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)","grant_id":"P30-CA015704","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA023766","title":null},{"funder_name":"U.S. Department of Health &amp; 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