CD147促进Foxp3表达进而维持Treg细胞免疫抑制功能的机制研究

CD147 is a transmembrane glycoprotein that is overexpressed in many tumor tissues. In addition, there are close relationships between CD147 and lymphocytes, and the most important is that it can regulate the development and functional stability of T cells. The researches about Treg cells and CD147 had a slow development. In 2011, Therese Solstad et al found that CD147 can be used as a classification marker about human CD4+Foxp3+ T cell population by proteomics analysis and flow cytometry, and it can be used as a direct marker of activated Treg cells,which is the most representative. The study of the relationship between CD147 and Treg cells was limited to in vitro induction and cell level, but we found in experiments that Treg cells in thymus and peripheral tissues were all changed in mice that specifically knocked out CD147 on T cells, which indicating that CD147 may play an important role in the regulation of Treg cell development or stability. This topic will use Treg cell-specific knockout CD147 mouse model to clarify the role of CD147 in the regulation of Treg cell function stability and its related molecular mechanisms; and the project will verify that the role of CD147 in maintaining Foxp3 expression of Treg cell whether has an impact on tumor development by construction of mouse melanoma model. We hope to provide a strong theoretical support and potential therapeutic targets for future clinical treatment.

CD147 是在许多肿瘤组织中高表达的跨膜糖蛋白，其与淋巴细胞的关系密切，其中最重要的是可以调节T细胞的发育和功能。Treg与CD147关系的研究一直进行的很缓慢，最具代表性的是CD147可以作为人CD4+Foxp3+T细胞亚群的分类标志和活化Treg细胞的一标志。CD147与Treg细胞之间关系的研究仅限于体外诱导和细胞水平上，而我们在实验中发现T细胞上特异性敲除CD147小鼠的胸腺和外周组织中Treg细胞均发生变化，提示CD147可能在调节Treg细胞发育或稳定性方面具有重要的作用。本课题将利用Treg细胞特异性敲除CD147的小鼠模型，旨在弄清CD147在调节Treg细胞功能稳定方面的作用及其相关的分子机制；并通过构建小鼠黑色素瘤模型，体内验证CD147对Treg细胞Foxp3表达的维持作用是否影响肿瘤的发生发展，希望能为以后的临床治疗方案的制定提供有力的理论支持和潜在的治疗靶点。

调节性T细胞（Treg）在免疫耐受和维持免疫稳态中起中心作用，需要严格控制其抑制功能，以建立平衡的免疫反应。Foxp3是Treg谱系特定的转录因子，对Treg细胞的发育、功能和稳定性至关重要。越来越多的研究表明Foxp3的表达和活性受翻译后修饰的调控，通过细胞内调控因子的活性建立对Treg细胞和Foxp3蛋白稳定性的进行适当调控。然而，Treg细胞研究的一个关键领域仍然是了解细胞外信号调节Foxp3的表达、稳定性和功能的机制，也就是机体微环境是否参与了Treg细胞稳定性的维持。.近期，空军军医大学第一附属医院临床免疫科朱平教授团队发现Treg需要细胞-细胞间的相互作用来维持Foxp3蛋白的稳定，包括Treg-Treg细胞接触和Treg-other细胞接触，这种相互作用由CD147-CD98介导。研究发现CD147对于维持Treg细胞的稳定性至关重要。T细胞上特异敲除CD147的小鼠外周Foxp3+ Treg细胞数量明显降低，CD147的缺失并不是影响了Foxp3的转录，而是加快了Foxp3蛋白的降解。具体机制是Treg细胞表面的CD147受到体内微环境中广泛表达的CD98的刺激，CD147的胞内结构域结合CDK2并将其保留在膜附近，导致Foxp3去磷酸化并阻止Foxp3降解。此外，无论在病理还是生理条件下，Foxp3+ Treg的分布均取决于微环境中CD98的表达。在机体内部微环境中，CD98是一种广泛表达的膜蛋白，甚至在T细胞上也有表达，因此可以认为是一种广泛存在的环境因子。因此，认为Treg细胞在发育形成后，需要在CD98存在的特定环境中稳定发挥功能。另外，研究中还构建了人源化小鼠的过继转移结肠炎模型，CD147highTreg细胞治疗能显著抑制肠炎表型，并且小鼠体内Treg细胞数量稳定，提示CD147highTreg细胞是治疗自身免疫性疾病的潜在的有效方法。

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