Anastasia I. Kousa, Lorenz Jahn, Kelin Zhao, Angel E. Flores, Dante Acenas II, Emma Lederer, Kimon V. Argyropoulos, Andri L. Lemarquis, David Granadier, Kirsten Cooper, Michael D’Andrea, Julie M. Sheridan, Jennifer Tsai, Lisa Sikkema, Amina Lazrak, Katherine Nichols, Nichole Lee, Romina Ghale, Florent Malard, Hana Andrlova, Enrico Velardi, Salma Youssef, Marina Burgos da Silva, Melissa Docampo, Roshan Sharma, Linas Mazutis, Verena C. Wimmer, Kelly L. Rogers, Susan DeWolf, Brianna Gipson, Antonio L. C. Gomes, Manu Setty, Dana Pe’er, Laura Hale, Nancy R. Manley, Daniel H. D. Gray, Marcel R. M. van den Brink, Jarrod A. Dudakov
{"title":"与年龄有关的上皮缺陷限制了胸腺功能和再生","authors":"Anastasia I. Kousa, Lorenz Jahn, Kelin Zhao, Angel E. Flores, Dante Acenas II, Emma Lederer, Kimon V. Argyropoulos, Andri L. Lemarquis, David Granadier, Kirsten Cooper, Michael D’Andrea, Julie M. Sheridan, Jennifer Tsai, Lisa Sikkema, Amina Lazrak, Katherine Nichols, Nichole Lee, Romina Ghale, Florent Malard, Hana Andrlova, Enrico Velardi, Salma Youssef, Marina Burgos da Silva, Melissa Docampo, Roshan Sharma, Linas Mazutis, Verena C. Wimmer, Kelly L. Rogers, Susan DeWolf, Brianna Gipson, Antonio L. C. Gomes, Manu Setty, Dana Pe’er, Laura Hale, Nancy R. Manley, Daniel H. D. Gray, Marcel R. M. van den Brink, Jarrod A. Dudakov","doi":"10.1038/s41590-024-01915-9","DOIUrl":null,"url":null,"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. Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7000,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01915-9.pdf","citationCount":"0","resultStr":"{\"title\":\"Age-related epithelial defects limit thymic function and regeneration\",\"authors\":\"Anastasia I. Kousa, Lorenz Jahn, Kelin Zhao, Angel E. Flores, Dante Acenas II, Emma Lederer, Kimon V. Argyropoulos, Andri L. Lemarquis, David Granadier, Kirsten Cooper, Michael D’Andrea, Julie M. Sheridan, Jennifer Tsai, Lisa Sikkema, Amina Lazrak, Katherine Nichols, Nichole Lee, Romina Ghale, Florent Malard, Hana Andrlova, Enrico Velardi, Salma Youssef, Marina Burgos da Silva, Melissa Docampo, Roshan Sharma, Linas Mazutis, Verena C. Wimmer, Kelly L. Rogers, Susan DeWolf, Brianna Gipson, Antonio L. C. Gomes, Manu Setty, Dana Pe’er, Laura Hale, Nancy R. Manley, Daniel H. D. Gray, Marcel R. M. van den Brink, Jarrod A. Dudakov\",\"doi\":\"10.1038/s41590-024-01915-9\",\"DOIUrl\":null,\"url\":null,\"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. Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.\",\"PeriodicalId\":19032,\"journal\":{\"name\":\"Nature Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-08-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.nature.com/articles/s41590-024-01915-9.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s41590-024-01915-9\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-024-01915-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Age-related epithelial defects limit thymic function and regeneration
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. Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.