Morimoto Junko, Matsumoto Minoru, Oya Takeshi, Tsuneyama Koichi, Matsumoto Mitsuru
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima, Japan.
Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
J Immunol. 2023 Jun 1;210(11):1653-1666. doi: 10.4049/jimmunol.2200780.
Regulatory T cells (Tregs) are produced in the thymus to establish self-tolerance, and agonistic stimuli by self-Ags play a pivotal role in this process. Although two types of APCs, medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), are responsible for presenting self-Ags together with costimulatory/cytokine signals, the distinct role of each APC in producing Tregs remains enigmatic. We have approached this issue by depleting the mTECs and DCs using mice expressing diphtheria toxin receptors driven by Aire and CD11c promoters, respectively. Depletion of mTECs showed an effect on Treg production quantitatively and qualitatively more profound than that of DCs followed by the development of distinct organ-specific autoimmune lesions in the hosts. Because self-Ags produced by mTECs are transferable to DCs through a process known as Ag transfer, we monitored the process of Ag transfer using mice expressing GFP from TECs. Although GFP expressed from total TECs was effectively transferred to DCs, GFP expressed from cortical TECs was not, suggesting that mTECs are the predominant source of self-Ags. We also found that GFP expressed not only from mature mTECs but also from immature mTECs was transferred to DCs, suggesting that a broad spectrum of molecules were subjected to Ag transfer during mTEC development. Interestingly, the numbers of recirculating non-Tregs producing IL-2, an important source for Treg expansion in the thymus, were reduced only in the mTEC-depleted mice. These results suggested the cooperative but distinct role of mTECs and DCs in the production of Tregs to avoid autoimmunity.
调节性T细胞（Tregs）在胸腺中产生以建立自身耐受性，自身抗原的激动刺激在这一过程中起关键作用。尽管两种抗原呈递细胞，即髓质胸腺上皮细胞（mTECs）和树突状细胞（DCs），负责呈递自身抗原以及共刺激/细胞因子信号，但每种抗原呈递细胞在产生Tregs中的独特作用仍不清楚。我们通过分别使用由Aire和CD11c启动子驱动表达白喉毒素受体的小鼠来耗尽mTECs和DCs，从而解决了这个问题。mTECs的耗尽对Treg产生的影响在数量和质量上都比DCs的耗尽更深远，随后宿主中出现了明显的器官特异性自身免疫性病变。由于mTECs产生的自身抗原可通过一种称为抗原转移的过程转移到DCs，我们使用从TECs表达绿色荧光蛋白（GFP）的小鼠监测了抗原转移过程。尽管从总TECs表达的GFP有效地转移到了DCs，但从皮质TECs表达的GFP却没有，这表明mTECs是自身抗原的主要来源。我们还发现，不仅从成熟mTECs表达的GFP，而且从未成熟mTECs表达的GFP都转移到了DCs，这表明在mTEC发育过程中有广泛的分子参与了抗原转移。有趣的是，产生白细胞介素-2（胸腺中Treg扩增的重要来源）的循环非Tregs数量仅在mTEC耗尽的小鼠中减少。这些结果表明mTECs和DCs在产生Tregs以避免自身免疫方面具有协同但不同的作用。
