Department of Neurology, Methodist Neurological Institute, The Methodist Hospital, Houston, TX 77030, USA.
Neurobiol Dis. 2012 Dec;48(3):418-28. doi: 10.1016/j.nbd.2012.07.008. Epub 2012 Jul 17.
Activated microglia and infiltrating lymphocytes are neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motoneuron disease. Although both cell types play pivotal roles in the ALS pathogenic process, the interactions between microglia and lymphocytes, specifically regulatory CD4+CD25High T lymphocytes (Tregs) and cytotoxic CD4+CD25- T lymphocytes (Teffs), have not been addressed. When co-cultured with mSOD1 adult microglia, mSOD1 Tregs suppressed the cytotoxic microglial factors NOX2 and iNOS through an IL-4-mediated mechanism, whereas Teffs were only minimally effective; IL-4 inhibitory antibodies blocked the suppressive function of mSOD1 Tregs, and conditioned media from mSOD1 Tregs or the addition of IL-4 reduced microglial NOX2 expression. During the stable disease phase, the total number of Tregs, specifically the numbers of CD4+CD25HighIL-4+, CD4+CD25HighIL-10+ and CD4+CD25HighTGF-β+ Tregs, were increased in ALS mice compared with WT mice; Tregs isolated during this phase reduced Teff proliferation. In contrast, during the rapidly progressing phase, the number of mSOD1 Tregs decreased while the proliferation of mSOD1 Teffs increased. The combination of IL-4, IL-10, and TGF-β was required to inhibit the proliferation of mSOD1 Teffs by mSOD1 Tregs that were isolated during the slow phase, while inhibition of mSOD1 Teffs by mSOD1 Tregs during the rapid phase, as well as WT Teffs, was not dependent on these factors. Thus, mSOD1 Tregs at the slow phase suppressed microglial toxicity and SOD1 Teff proliferation through different mechanisms; microglial activation was suppressed through IL-4 whereas mSOD1 Teffs were suppressed by IL-4, IL-10 and TGF-β. These data suggest that mSOD1 Tregs contribute to the slowly progressing phase in ALS mice and may offer a novel therapeutic option for ALS patients.
激活的小胶质细胞和浸润的淋巴细胞是肌萎缩侧索硬化症（ALS）的神经病理学标志，ALS 是一种致命的运动神经元疾病。虽然这两种细胞类型在 ALS 发病过程中都起着关键作用，但小胶质细胞和淋巴细胞之间的相互作用，特别是调节性 CD4+CD25HighT 淋巴细胞（Tregs）和细胞毒性 CD4+CD25-T 淋巴细胞（Teffs），尚未得到解决。当与 mSOD1 成年小胶质细胞共培养时，mSOD1 Tregs 通过 IL-4 介导的机制抑制了细胞毒性小胶质细胞因子 NOX2 和 iNOS，而 Teffs 的作用则很小；IL-4 抑制性抗体阻断了 mSOD1 Tregs 的抑制功能，而 mSOD1 Tregs 的条件培养基或 IL-4 的添加减少了小胶质细胞的 NOX2 表达。在稳定疾病阶段，与 WT 小鼠相比，ALS 小鼠的 Tregs 总数，特别是 CD4+CD25HighIL-4+、CD4+CD25HighIL-10+和 CD4+CD25HighTGF-β+Tregs 的数量增加；在此阶段分离的 Tregs 减少了 Teff 的增殖。相比之下，在快速进展阶段，mSOD1 Tregs 的数量减少，而 mSOD1 Teffs 的增殖增加。在缓慢阶段分离的 mSOD1 Tregs 抑制 mSOD1 Teffs 的增殖需要 IL-4、IL-10 和 TGF-β 的组合，而在快速阶段抑制 mSOD1 Tregs 和 WT Teffs 的增殖则不依赖于这些因素。因此，在缓慢阶段的 mSOD1 Tregs 通过不同的机制抑制小胶质细胞毒性和 SOD1 Teff 的增殖；通过 IL-4 抑制小胶质细胞激活，而通过 IL-4、IL-10 和 TGF-β 抑制 mSOD1 Teffs。这些数据表明，mSOD1 Tregs 有助于 ALS 小鼠的缓慢进展阶段，并且可能为 ALS 患者提供一种新的治疗选择。
