Ohigashi Izumi, White Andrea J, Yang Mei-Ting, Fujimori Sayumi, Tanaka Yu, Jacques Alison, Kiyonari Hiroshi, Matsushita Yosuke, Turan Sevilay, Kelly Michael C, Anderson Graham, Takahama Yousuke
Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima 770-8503, Japan.
Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
bioRxiv. 2023 Dec 8:2023.10.03.560657. doi: 10.1101/2023.10.03.560657.
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. 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.
胸腺髓质上皮细胞建立免疫自我耐受性，并包含多种细胞亚群。功能相关的髓质胸腺上皮细胞（mTECs）包括一个呈递自身抗原的亚群，该亚群表现出由核蛋白Aire促进的全基因组杂乱基因表达，并且类似于包括黏膜簇状细胞在内的胸腺外细胞的镶嵌体。另一个mTEC亚群产生趋化因子CCL21，从而将来自皮质的阳性选择胸腺细胞吸引到髓质。呈递自身抗原和吸引胸腺细胞的mTEC亚群对于自我耐受性都是必不可少的。在这里，我们确定了一条发育途径，通过该途径mTECs在功能上不同的亚群中获得其多样性。我们表明，表达CCL21的mTECs在胸腺发育早期出现。命运图谱分析表明，呈递自身抗原的mTECs，包括表达Aire的mTECs和胸腺簇状细胞起源于表达CCL21的细胞。在重组胸腺实验中验证了表达CCL21的胚胎mTECs的分化能力。这些结果表明，表达CCL21的胚胎mTECs具有产生呈递自身抗原的mTECs的发育潜力，揭示了吸引胸腺细胞的亚群向呈递自身抗原的亚群的顺序转化有助于在胸腺髓质上皮细胞中组装功能多样性。
