Department of Neurology, Thomas Jefferson University, 900 Walnut Street, JHN 300, Philadelphia, PA 19107, USA.
Apoptosis. 2013 Sep;18(9):1106-19. doi: 10.1007/s10495-013-0870-2.
Recent data show that anti-CD20 therapy is effective for some autoimmune diseases, including multiple sclerosis (MS). However, the efficacy of anti-CD20 therapy for MS is largely limited because anti-CD20 antibodies target only B cells. In previous studies, we have investigated the function of MS4a4B, a novel CD20 homologue, in T cell proliferation. Here, we found that MS4a4B regulates not only T cell proliferation but also T cell apoptosis. Knockdown of MS4a4B by MS4a4B-siRNA or MS4a4B-shRNA-expressing vector promoted apoptosis in primary T cells and T32 cell line. In contrast, vector-driven over-expression of MS4a4B reduced apoptosis in EL-4 cells. Machinery analysis showed that MS4a4B-mediated T cell survival was associated with decreased activity of caspases 3, 8 and 9. Interestingly, binding of anti-MS4a4B antibodies to T cells induced activated T cells to undergo apoptosis. To test whether anti-MS4a4B antibody interferes with MS4a4B-mediated protection of T cells, we injected anti-MS4a4B antibodies into mice with experimental autoimmune encephalomyelitis (EAE). The results show that anti-MS4a4B treatment ameliorated the severity of EAE, accompanied by decreased Th1 and Th17 cell responses and reduced levels of pro-inflammatory cytokines in the central nervous system, suggesting that MS4a4B may serve as a target of antibody-based therapy for T cell-mediated diseases.
最近的数据表明，抗 CD20 治疗对一些自身免疫性疾病有效，包括多发性硬化症（MS）。然而，抗 CD20 治疗 MS 的疗效在很大程度上受到限制，因为抗 CD20 抗体仅针对 B 细胞。在之前的研究中，我们研究了新型 CD20 同源物 MS4a4B 在 T 细胞增殖中的功能。在这里，我们发现 MS4a4B 不仅调节 T 细胞增殖，还调节 T 细胞凋亡。MS4a4B-siRNA 或表达 MS4a4B-shRNA 的载体敲低 MS4a4B 可促进原代 T 细胞和 T32 细胞系的凋亡。相反，载体驱动的 MS4a4B 过表达可减少 EL-4 细胞的凋亡。机制分析表明，MS4a4B 介导的 T 细胞存活与 Caspase 3、8 和 9 的活性降低有关。有趣的是，抗 MS4a4B 抗体与 T 细胞的结合诱导激活的 T 细胞发生凋亡。为了测试抗 MS4a4B 抗体是否干扰 MS4a4B 介导的 T 细胞保护，我们将抗 MS4a4B 抗体注入实验性自身免疫性脑脊髓炎（EAE）小鼠中。结果表明，抗 MS4a4B 治疗可改善 EAE 的严重程度，同时伴有 Th1 和 Th17 细胞反应的降低以及中枢神经系统中促炎细胞因子水平的降低，表明 MS4a4B 可能成为基于抗体的 T 细胞介导疾病治疗的靶点。
