i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Cell Death Dis. 2024 May 21;15(5):352. doi: 10.1038/s41419-024-06728-0.
Within the thymus, thymic epithelial cells (TECs) create dedicated microenvironments for T cell development and selection. Considering that TECs are sensitive to distinct pathophysiological conditions, uncovering the molecular elements that coordinate their thymopoietic role has important fundamental and clinical implications. Particularly, medullary thymic epithelial cells (mTECs) play a crucial role in central tolerance. Our previous studies, along with others, suggest that mTECs depend on molecular factors linked to genome-protecting pathways, but the precise mechanisms underlying their function remain unknown. These observations led us to examine the role of Foxo3, as it is expressed in TECs and involved in DNA damage response. Our findings show that mice with TEC-specific deletion of Foxo3 (Foxo3) displayed a disrupted mTEC compartment, with a more profound impact on the numbers of CCL21 and thymic tuft mTEC subsets. At the molecular level, Foxo3 controls distinct functional modules in the transcriptome of cTECs and mTECs under normal conditions, which includes the regulation of ribosomal biogenesis and DNA damage response, respectively. These changes in the TEC compartment resulted in a reduced total thymocyte cellularity and specific changes in regulatory T cell and iNKT cell development in the Foxo3 thymus. Lastly, the thymic defects observed in adulthood correlated with mild signs of altered peripheral immunotolerance in aged Foxo3 mice. Moreover, the deficiency in Foxo3 moderately aggravated the autoimmune predisposition observed in Aire-deficient mice. Our findings highlight the importance of Foxo3 in preserving the homeostasis of TECs and in supporting their role in T cell development and tolerance.
在胸腺中，胸腺上皮细胞 (TEC) 为 T 细胞的发育和选择创造了专门的微环境。鉴于 TEC 对不同的病理生理条件敏感，揭示协调其胸腺生成作用的分子元素具有重要的基础和临床意义。特别是，髓质胸腺上皮细胞 (mTEC) 在中枢耐受中发挥着关键作用。我们之前的研究以及其他研究表明，mTEC 依赖于与基因组保护途径相关的分子因子，但它们功能的确切机制尚不清楚。这些观察结果促使我们研究 Foxo3 的作用，因为它在 TEC 中表达并参与 DNA 损伤反应。我们的研究结果表明，TEC 特异性缺失 Foxo3 (Foxo3) 的小鼠显示出 mTEC 区室中断，对 CCL21 和胸腺簇状 mTEC 亚群的数量影响更严重。在分子水平上，Foxo3 在正常条件下控制 cTEC 和 mTEC 转录组中的不同功能模块，分别包括核糖体生物发生和 DNA 损伤反应的调节。TEC 区室的这些变化导致总胸腺细胞细胞数量减少，Foxo3 胸腺中的调节性 T 细胞和 iNKT 细胞发育出现特定变化。最后，成年期观察到的胸腺缺陷与老年 Foxo3 小鼠外周免疫耐受改变的轻微迹象相关。此外，Foxo3 的缺乏适度加重了 Aire 缺陷型小鼠中观察到的自身免疫易感性。我们的研究结果强调了 Foxo3 在维持 TEC 稳态和支持其在 T 细胞发育和耐受中的作用的重要性。
