Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms.
Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms.
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DOI：
10.1016/j.nbd.2012.07.008
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发表时间：
2012-12
影响因子：
6.1
通讯作者：
Appel SH
中科院分区：
文献类型：
--
作者：
Zhao W;Beers DR;Liao B;Henkel JS;Appel SH
活化的小胶质细胞和浸润淋巴细胞是肌萎缩侧索硬化症（ALS）的神经病理学特征，这是一种致命的运动神经元疾病。尽管这两种细胞类型在ALS的发病过程中都起着关键作用，但小胶质细胞与淋巴细胞，特别是调节性CD4+CD25高T淋巴细胞（Tregs）和细胞毒性CD4+CD25−T淋巴细胞（Teffs）之间的相互作用尚未得到解决。当与mSOD1成人小胶质细胞共培养时，mSOD1 Tregs通过il -4介导的机制抑制细胞毒性小胶质细胞因子NOX2和iNOS，而Teffs仅具有最低限度的作用；IL-4抑制抗体阻断了mSOD1 Tregs的抑制功能，mSOD1 Tregs的条件培养基或IL-4的加入降低了小胶质细胞NOX2的表达。在疾病稳定期，ALS小鼠的treg总数，特别是CD4+CD25HighIL-4+、CD4+CD25HighIL-10+和CD4+CD25HighTGF-β+ treg的数量较WT小鼠增加；在这一阶段分离的Tregs降低了Teffs的增殖。相反，在快速进展阶段，mSOD1 treg的数量减少，而mSOD1 Teffs的增殖增加。IL-4、IL-10和TGF-β的联合作用可以抑制慢期分离的mSOD1 Tregs对mSOD1 Teffs的增殖，而快速期mSOD1 Tregs对mSOD1 Teffs以及WT Teffs的抑制作用则不依赖于这些因素。因此，慢期mSOD1 Tregs通过不同机制抑制小胶质细胞毒性和SOD1 Teffs增殖；IL-4抑制小胶质细胞的激活，而IL-4、IL-10和TGF-β抑制mSOD1 Teffs。这些数据表明，mSOD1 Tregs参与了ALS小鼠的缓慢进展阶段，并可能为ALS患者提供一种新的治疗选择。
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 Teffs 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 Teffs 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.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
5.3
作者：
Liao, Bing;Zhao, Weihua;Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
通讯作者：
Appel, Stanley H.
DOI：
10.1093/brain/awr074
发表时间：
2011-05
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Beers DR;Henkel JS;Zhao W;Wang J;Huang A;Wen S;Liao B;Appel SH
通讯作者：
Appel SH
影响因子：
9.9
作者：
Alexianu, ME;Kozovska, M;Appel, SH
通讯作者：
Appel, SH
影响因子：
4.4
作者：
Baecher-Allan, Clare;Wolf, Elizabeth;Haller, David A.
通讯作者：
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