Loss of Keratin 76 in Thymic Epithelial Cells affects Skin Tissue Self-Antigens presentation in the Thymus and disrupts T cell tolerance

胸腺上皮细胞中角蛋白 76 的丢失会影响胸腺中皮肤组织自身抗原的呈现并破坏 T 细胞耐受性

• 批准号: 2442036
• 金额: --
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2442036
• 关键词: Loss; Keratin; 76; Thymic; Epithelial

"Keratins are cytoskeletal proteins expressed in epithelial cells, including medullary thymic epithelial cells (mTECs). Recent studies have uncovered a role for keratins in regulating immunity (Hobbs et al., 2015). Keratin76 (Krt76) is expressed in epithelial cells of the oral cavity, squamous stomach and thymus, and was shown to play an immunomodulatory role in oral and gastric cancer (Sequeira et al., 2018). Krt76-/- adult mice display a chronic inflammation phenotype, however, it remains unclear how thymic epithelial cells (TECs) expressing Krt76 are interacting with and regulating the immune system.I aim to investigate how loss of Krt76 specifically in the thymus impacts T cell development and demonstrate its role in communicating with cellular components to regulate the expression of skin-specific tissue self-antigens (TSAs) within the thymus. We identified co-expression of Krt76 amongst other terminally differentiated mTEC markers and in human and mice Hassall's Corpuscles, unique thymic structures with an unclear function. We transplanted foetal Krt76-/- thymi into the renal capsule of athymic nude mice which confirmed that adult Krt76-/- inflammatory phenotype was driven by Krt76 disruption specifically in the thymus. We hypothesised that Krt76+ TECs may be responsible for the expression of TSAs, based on the recent study by Michelson et al. (Cell 2022). Analysis of their published dataset indicated expression of specific skin TSAs by Krt76+ mTECs. Additionally, we carried out scRNA-seq of Krt76-/- thymi to investigate the cellular and molecular differences in the Krt76-/- thymi, and assessed the molecular mechanisms regulating these changes. Additionally, flow cytometry and immunohistochemistry analysis revealed higher numbers of effector T cells in the periphery of young adult Krt76-/- mice, but not at earlier timepoints. Our results confirm that keratins in the thymus can impact the maturation of T cells, in particular by priming T cells specifically against skin TSAs. This study highlights the fundamental role of keratins in tightly regulated immunological processes. This study places Krt76+ TECs in direct communication with skin immune homeostasis, which could present as a major new target for future therapeutic interventions."

角蛋白是在包括胸腺髓质上皮细胞在内的上皮细胞中表达的细胞骨架蛋白。最近的研究发现了角蛋白在调节免疫中的作用(Hobbs等人，2015年)。Keratin76(Krt76)表达于口腔、鳞状胃和胸腺的上皮细胞，并被证明在口腔癌和胃癌中发挥免疫调节作用(Sequeira等人，2018年)。Krt76-/-成年小鼠表现为慢性炎症表型，然而，表达Krt76的胸腺上皮细胞(TECs)如何与免疫系统相互作用并调节免疫系统尚不清楚。我的目标是研究Krt76在胸腺中的特异性丢失如何影响T细胞的发育，并证明其在与细胞成分沟通以调节胸腺内皮肤特异性组织自身抗原(TSA)表达方面的作用。我们发现Krt76和其他终末分化的mTEC标志物以及在人类和小鼠的哈撒尔小体中共同表达，这是一种独特的胸腺结构，功能不清楚。我们将胎儿Krt76-/-胸腺移植到裸鼠的肾被膜中，证实了成人Krt76-/-炎症表型是由胸腺中Krt76的破坏所驱动的。根据Michelson等人最近的研究，我们推测Krt76+TECs可能与TSA的表达有关。(单元格2022)。对他们发表的数据集的分析表明，Krt76+mTEC表达了特定的皮肤TSA。此外，我们对Krt76-/-胸腺进行了scRNA-seq，以研究Krt76-/-胸腺的细胞和分子差异，并评估了调节这些变化的分子机制。此外，流式细胞术和免疫组织化学分析显示，年轻成年Krt76-/-小鼠的外周效应性T细胞数量较多，但在较早的时间点没有。我们的结果证实，胸腺中的角蛋白可以影响T细胞的成熟，特别是通过启动针对皮肤TSA的T细胞。这项研究强调了角蛋白在严密调控的免疫过程中的基础作用。这项研究将Krt76+TECs置于与皮肤免疫动态平衡的直接通信中，这可能成为未来治疗干预的主要新靶点。“