Clarification of the role of CD8^+CD122^+ regulatory T cells in vivo and development of their clinical applications

1. CD 8 ^+ CD 122 ^+调节性T细胞的作用机制我们利用体外培养系统研究了小鼠CD 8 ^+ CD 122 ^+调节性T细胞如何抑制其靶细胞。结果，我们发现这些调节性T细胞直接识别活化的T细胞，而不需要抗原呈递细胞的干预，并调节它们。MHC Ⅰ类分子与T细胞受体、CD 28分子与CD 80/CD 86分子的相互作用在调控过程中起重要作用。已经识别其靶细胞的调节性T细胞成为活跃的调节性细胞，并通过产生IL-10.2来调节它们。CD 8 ^+ CD 122 ^+调节性T细胞在自身免疫性疾病中的作用我们利用实验性自身免疫性脑脊髓炎（Experimental Autoimmune Encephalomyelitis，EAE）小鼠模型，研究了CD 8 ^+ CD 122 ^+调节性T细胞在EAE中的作用。用抗CD 122抗体去除CD 8 ^+ CD 122 ^+调节性T细胞的小鼠，EAE的症状持续6周以上没有改善。另一方面，TR ...更多信息 将CD 8 ^+ CD 122 ^+调节性T细胞转移到用抗CD 122抗体治疗的小鼠体内，并使EAE症状持续在峰值水平，可显著地使EAE症状迅速减轻。从而明确证明了CD 8 ^+ CD 122 ^+调节性T细胞在以免疫系统异常为基础的疾病的恢复过程中起着重要作用.寻找人类调节性T细胞由于人类中不存在CD 8 ^+ CD 122 ^+细胞，我们需要使用除CD 122之外的其他标志物来寻找人类CD 8 ^+调节性T细胞。我们利用DNA微阵列分析比较了CD 8 ^+ CD 122 ^+细胞和CD 8 ^+ CD 122 ^-细胞的基因表达谱。我们发现CXCR 3是一个候选基因，并且在小鼠CD 8 ^+细胞中CD 122和CXCR 3的表达有很好的相关性。也有表达CXCR 3的人CD 8 ^+细胞，并且这种CD 8 ^+ CXCR 3 ^+细胞显示出免疫调节活性，例如抑制CD 8 ^+ CXCR 3细胞产生IFN_γ。因此，CD 8 ^+ CXCR 3 ^+细胞作为调节性T细胞发挥作用，相当于鼠CD 8 ^+ CD 122 ^+细胞。少

1. Mechanism of the effect of CD8^+CD122^+ regulatory T cellsWe investigated how murine CD8^+CD122^+ regulatory T cells suppress their target cells by using in vitro culture systems. As a result, we found that these regulatory T cells directly recognized activated T cells without intervention of antigen-presenting cells and regulated them. The interactions between MHC class I and T cell receptor and between CD28 and CD80/CD86 were important in the process of regulation. The regulatory T cells that had recognized their target cells became active regulatory cells and regulated them by producing IL-10.2. Effect of CD8^+CD122^+ regulatory T cells on autoimmune diseasesWe investigated on the effect of CD8^+CD122^+ regulatory T cells using murine model of EAE (Experimental Autoimmune Encephalomyelitis). In mice that had been treated with anti-CD122 antibody that depleted CD8^+CD122^+ regulatory T cells, symptoms of EAE continued for more than6 weeks without improvement. On the other hand, tr … More ansfer of CD8^+CD122^+ regulatory T cells into those mice that had been treated with anti-CD122 antibody and continued the EAE symptoms at thepeak level dramatically caused the quick reduction of EAE symptoms. Thus, it was clearly proved that CD8^+CD122^+ regulatory T cells play an important role in the recovery from the disease that based on the anomaly of immune system.3. Search for human regulatory T cellsBecause there are no CD8^+CD122^+ cells in human, we needed to search human CD8^+ regulatory T cells using other markers than CD122. We performed DNA micro-array analysis to compare the gene expression profile between CD8^+CD122^+ cells and CD8^+CD122^- cells. We found CXCR3 as a candidate gene, and actually the expression of CD122and that of CXCR3was well correlated in mouse CD8^+cells. There are also human CD8^+ cells that express CXCR3and such CD8^+CXCR3^+ cells showed immune regulating activity such as suppressing the production of IFN_γ from the CD8^+CXCR3 cells. Thus, CD8^+CXCR3^+ cells work as regulatory T cells that correspond to murine CD8^+CD122^+ cells. Less