Using single-cell RNA (including TCR) sequencing and single-molecule fluorescence in situ hybridization, Park et al. constructed a comprehensive human thymus cell atlas across the human lifespan. Transcriptomic analysis revealed the cellular composition of thymic microenvironment, predicted the trajectory of T cell development from early progenitor to diverse T cell types, and identified a novel population of GNG4+CD8αα+ T cells co-located with XCR1+ cDC1. Comparison of TCR repertoire between cell types revealed the dynamics and biases of recombination and the impact of functional selection on both the α and β loci.
Contributed by Shishir Pant
ABSTRACT: The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8alphaalpha(+) T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.
Author Info: (1) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (2) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon
Author Info: (1) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (2) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (3) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (4) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (5) Faculty of Medicine and Health Sciences, Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium. Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium. (6) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK. (7) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (8) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (9) Epithelial Stem Cell Biology and Regenerative Medicine Laboratory, Francis Crick Institute, London NW1 1AT, UK. Great Ormond Street Institute of Child Health, University College London, London, UK. (10) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (11) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (12) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (13) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (14) Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QQ, UK. (15) John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK. (16) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (17) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (18) Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium. (19) Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. (20) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (21) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (22) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (23) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Department of Adult Congenital Heart Disease and Paediatric Cardiology/Cardiothoracic Surgery, Freeman Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK. (24) Department of Adult Congenital Heart Disease and Paediatric Cardiology/Cardiothoracic Surgery, Freeman Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK. (25) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (26) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (27) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (28) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (29) Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. (30) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (31) Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (32) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (33) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (34) John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK. WT-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre Cambridge Biomedical Campus, Cambridge CB2 0AW, UK. (35) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. (36) Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium. (37) Epithelial Stem Cell Biology and Regenerative Medicine Laboratory, Francis Crick Institute, London NW1 1AT, UK. Great Ormond Street Institute of Child Health, University College London, London, UK. Institute of Immunity and Transplantation, University College London, London, UK. (38) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Paediatrics, University of Cambridge, Cambridge CB2 0SP, UK. (39) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QQ, UK. Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK. (40) Faculty of Medicine and Health Sciences, Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium. m.a.haniffa@newcastle.ac.uk tom.taghon@ugent.be st9@sanger.ac.uk. Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium. (41) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. m.a.haniffa@newcastle.ac.uk tom.taghon@ugent.be st9@sanger.ac.uk. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK. (42) Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. m.a.haniffa@newcastle.ac.uk tom.taghon@ugent.be st9@sanger.ac.uk. Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK.
