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Abstract
The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.
The thymus is essential for T cell maturation and selection, and thymic defects result in severe immune problems. Here the authors identify a thymus cell population that is expandable in vitro, and can repopulate natural thymic matrix to generate tissue that supports mature T cell development in vitro and in vivo.
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1 Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); UCL Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
2 Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
3 Haematopoietic Stem Cell laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
4 Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); UCL Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy (GRID:grid.18887.3e) (ISNI:0000000417581884)
5 Bioinformatics Laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
6 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea (GRID:grid.37172.30) (ISNI:0000 0001 2292 0500)
7 UCL Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Histopathology, London, UK (GRID:grid.424537.3) (ISNI:0000 0004 5902 9895)
8 Immunosurveillance laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
9 IEO, European Institute of Oncology, IRCCS, Department of Experimental Oncology, Milan, Italy (GRID:grid.15667.33) (ISNI:0000 0004 1757 0843); University of Milan, Department of Oncology and Hemato-Oncology, Milan, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822)
10 IEO, European Institute of Oncology, IRCCS, Department of Experimental Oncology, Milan, Italy (GRID:grid.15667.33) (ISNI:0000 0004 1757 0843)
11 Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
12 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382)
13 Immunosurveillance laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); School of Immunology & Microbial Sciences, King’s College London, Peter Gorer Department of Immunobiology, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
14 Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); UCL Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)