Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in embryonic thymus medulla epithelium
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- Izumi Ohigashi
- Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima
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- Andrea J White
- Institute for Immunology and Immunotherapy, University of Birmingham
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- Mei-Ting Yang
- Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health
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- Sayumi Fujimori
- Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima
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- Yu Tanaka
- Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health
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- Alison Jacques
- Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health
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- Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research
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- Yosuke Matsushita
- Division of Genome Medicine, Institute of Advanced Medical Sciences, University of Tokushima
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- Sevilay Turan
- Sequencing Facility, Frederick National Laboratory for Cancer Research, National Cancer Institute
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- Michael C Kelly
- Single Cell Analysis Facility, Cancer Research Technology Program, National Cancer Institute, National Institutes of Health
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- Graham Anderson
- Institute for Immunology and Immunotherapy, University of Birmingham
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- Yousuke Takahama
- Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health
Description
<jats:p>Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.</jats:p>
Journal
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- eLife
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eLife 12 2024-03-11
eLife Sciences Publications, Ltd