CD226分子对I型调节性T细胞(Tr1)的调节及其在人MS(小鼠EAE)发病中的作用

The immunosuppressive properties of type I regulatory T cells (Tr1) are vital for the maintenance of peripheral immune tolerance. It has been demonstrated that CD4+CD49b+LAG-3+CD226+ are the surface markers of Tr1 cells. Among them, CD4, CD49b and LAG-3 are stably expressed on Tr1 cells, whereas the expression levels of CD226 are due to the variation of Tr1 cell functions. Our study showed that LeoA1, the mAb of CD226, significantly increased the percentage of CD4+CD49b+LAG-3+ Tr1 cells in PBMC CD4+T cells . Meanwhile, CD226 knockout mice showed significantly better outcome of experimental autoimmune encephalomyelitis (EAE) than that of wild type mice. The above results suggested that CD226 may play an important role in mediating EAE via the regulation of Tr1 cell differentiation, proliferation and function. In this study, firstly, we try to clarify the role of CD226 in Tr1 cells’ differentiation, proliferation and function. Secondly,to explore the molecular mechanisms of CD226 in regulating Tr1 cell differentiation. At last, to discuss the therapy possibility of CD226 modulating Tr1 cells in MS patients or EAE model mice. Our studies will not only provide the novel molecular mechanisms of Tr1 cell differentiation and function,but also expect to give the theoretical and experimental evidences for understanding and treating the Tr1 cell-related clinical diseases.

I型调节性T细胞(Tr1)的免疫抑制作用对于外周免疫耐受的形成至关重要。现已证实，Tr1的表面标记是CD4+CD49b+LAG-3+CD226+,其中CD4、CD49b和LAG-3等分子稳定表达在Tr1表面，而CD226分子的表达水平则随Tr1功能改变而发生变化。我们发现，CD226单克隆抗体LeoA1上调人外周血PBMC CD4+T细胞中CD4+CD49b+LAG-3+Tr1比例，CD226-/-小鼠EAE症状显著减轻，提示CD226分子通过调控Tr1的分化和功能参与EAE发病。本研究拟首先明确CD226对Tr1分化、增殖和功能的影响；阐明CD226调控Tr1分化的信号通路；最后，探讨通过改变CD226表达水平调控Tr1功能治疗人MS(小鼠EAE)的可行性。本课题不仅对深入阐明Tr1分化和功能的分子机制有重要意义，而且为Tr1相关的临床重要疾病发病机理和治疗策略提供新的理论和实验依据。

调节性T细胞在多种自身免疫性疾病中发挥重要作用。本课题深入研究了CD226分子调节Treg和Tr1分化和功能的分子机制和信号通路，探讨了其在小鼠实验性自身免疫性脑脊髓炎（EAE）和人视神经脊髓炎(NMOSD)等自身免疫性疾病发病中的作用，发现：①CD226分子促进Tr1分化、增强Tr1的抑制功能；②小鼠EAE模型中CD226分子通过调节CTLA-4和TIGIT表达影响Treg的抑制功能；③小鼠EAE模型中CD226分子通过Akt/Erk信号通路影响Treg增殖；④视神经脊髓炎谱系疾病患者Tr1和Treg上CD226分子表达水平发生改变，CD226分子在NMOSD发生发展中发挥了一定的作用。我们的研究结果为阐明调节性T细胞（Treg和Tr1）相关的临床重要疾病发病机理和制定新的治疗策略提供了新的理论和实验依据，具有很好的科学意义和应用前景。