Anastasia I. Kousa1,2,3†, Lorenz Jahn1†, Kelin Zhao4,5†, Angel E. Flores6‡, Dante Acenas II2,7‡, Emma Lederer2,7‡, Kimon V. Argyropoulos8‡, Andri Lemarquis1,3, David Granadier2, Kirsten Cooper2, Michael D’Andrea4,5, Julie M. Sheridan4, Jennifer Tsai1, Lisa Sikkema9,10, Amina Lazrak1, Katherine Nichols1, Nichole Lee1, Romina Ghale1, Florent Malard1,11, Hana Andrlova1, Enrico Velardi12, Salma Youssef1, Marina Burgos da Silva1, Melissa Docampo1, Roshan Sharma9, Linas Mazutis9, Verena C. Wimmer4,5, Kelly L. Rogers4,5, Susan DeWolf13, Brianna Gipson1, Antonio L.C. Gomes1, Manu Setty9,14, Dana Pe'er9, Laura Hale15, Nancy R. Manley6,16, Daniel H.D. Gray4,5*§, Marcel R.M. van den Brink1,3,13*§, Jarrod A. Dudakov2,7*§
1Program in Immunology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
2Translational Science and Therapeutics Division, and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
3City of Hope Los Angeles and National Medical Center, Duarte, CA, USA
4The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
5Department of Medical Biology, The University of Melbourne, Victoria, Australia
6Department of Genetics, University of Georgia, Athens, GA, USA
7Department of Immunology, University of Washington, Seattle, WA, USA
8Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
9Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
10Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
11INSERM U938, Centre de Recherche Saint-Antoine, Paris, Sorbonne Université, Paris, and Service d'Hématologie Clinique, AP-HP, Hôpital Saint-Antoine, Paris, France
12Division of Pediatric Hematology and Oncology, Bambino Gesù Children’s Hospital, IRCCS, Rome, 00146, Italy
13Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
14Basic Sciences Division & Translational Data Science Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
15Human Vaccine Institute, Duke University, Durham, NC, USA
16School of Life Sciences, Arizona State University, Phoenix, AZ, USA
†,‡,§These authors contributed equally to this work.
*Corresponding authors: [email protected]; [email protected]; [email protected]
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 non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC 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.
This repository includes Jupyter notebooks adapted from shunPykeR, dynamo, cellrank and cellchat GitHub repositories. Processed data to be used with these notebooks have been deposited in NCBI's Gene Expression Omnibus (GEO) and can be accessed through the GEO SuperSeries accession number GEO240020.
The app.R code that launches the ThymoSight R Shiny app is available at the thymosight GitHub repository. The server hosting the interactive app can be accessed at www.thymosight.org. The re-analyzed public datasets with added metadata that are used as input for the ThymoSight app are available at zenodo.