Sheridan et al. identified that subcapsular sinus lymphatic endothelial cells (LECs) archive antigens for the longest duration post-immunization, and defined transcriptional signatures associated with long-term antigen archiving. Antigen-high LECs exhibited increased endo-lysosomal activity and clathrin- and caveolin-mediated endocytosis, and sequential immunization further enhanced the antigen uptake and archiving capacity of LECs. Machine learning uncovered gene modules predictive of antigen archiving across mouse and human datasets, and these were validated in a CHIKV infection-mediated impaired antigen-archiving model.
Contributed by Shishir Pant
ABSTRACT: Lymph node (LN) lymphatic endothelial cells (LEC) actively acquire and archive foreign antigens. Here, we address questions of how LECs achieve durable antigen archiving and whether LECs with high levels of antigen express unique transcriptional programs. We use single cell sequencing in dissociated LN tissue and spatial transcriptomics to quantify antigen levels in LEC subsets and dendritic cell populations at multiple time points after immunization and determine that ceiling and floor LECs archive antigen for the longest duration. We identify, using spatial transcriptomics, antigen positive LEC-dendritic cell interactions. Using a prime-boost strategy we find increased antigen levels within LECs after a second immunization demonstrating that LEC antigen acquisition and archiving capacity can be improved over multiple exposures. Using machine learning we define a unique transcriptional program within archiving LECs that predicts LEC archiving capacity in independent mouse and human data sets. We test this modeling, showing we can predict lower levels of LEC antigen archiving in chikungunya virus-infected mice and demonstrate in vivo the accuracy of our prediction. Collectively, our findings establish unique properties of LECs and a defining transcriptional program for antigen archiving that can predict antigen archiving capacity in different disease states and organisms.
Author Info: (1) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (2) Department of Medicine, Division o
Author Info: (1) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (2) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (3) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (4) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (5) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (6) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (7) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (8) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (9) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (10) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (11) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (12) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (13) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (14) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Beth.tamburini@cuanschutz.edu. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. Beth.tamburini@cuanschutz.edu.
