Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells
Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells
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DOI：
10.4049/jimmunol.177.8.5041
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发表时间：
2006-10-15
影响因子：
4.4
通讯作者：
Sarin, Apurva
中科院分区：
文献类型：
--
作者：
Bheeshmachar, Geetha;Purushotaman, Divya;Sarin, Apurva
外周 T 细胞稳态是促进存活的因素与触发 Ag 反应性细胞缺失的因素之间的平衡的结果。细胞因子 IL-2 促进 T 细胞存活，而活性氧 (ROS) 则使 T 细胞对凋亡敏感。激活 T 细胞凋亡的两种途径（一种由 Fas 配体触发，另一种由细胞因子剥夺触发）依赖于 ROS，后者也受 Bcl-2 家族成员的调节。 Notch 家族蛋白调节后生动物中的多种细胞命运决定。 T 细胞中 Notch1 胞内结构域 (NICD) 的异位表达可抑制 Fas 诱导的细胞凋亡。根本机制尚不清楚，Notch 在调节细胞因子剥夺或忽视引发的细胞凋亡中的作用（如果有的话）尚未得到研究。在这项研究中，我们使用了Notch1/Fc嵌合体；一种针对 Notch1 的阻断抗体和 γ-分泌酶的化学抑制剂，用于研究 Notch 信号传导在小鼠来源的活化 T 细胞中的作用。我们发现，扰乱维持在 IL-2 中的活化 CD4(+)/CD8(+) T 细胞中的 Notch 信号传导会导致 ROS 积累、Akt/蛋白激酶 B 活性降低以及抗凋亡蛋白 Bcl-x(L) 表达，最终导致细胞凋亡。广谱氧化还原清除剂抑制细胞凋亡，但表达突变型 Fas 配体的 T 细胞对细胞凋亡敏感。基于 Notch 表达 (Notch(+)) 分离的活化 T 细胞富含 Bcl-x(L) 表达，并表现出对忽视或氧化应激引发的细胞凋亡的敏感性降低。此外，NICD 的强制表达可保护活化的 T 细胞免受细胞因子剥夺引发的细胞凋亡。总而言之，这些数据表明 Notch1 信号传导与活化 T 细胞的细胞因子依赖性存活相关。
Peripheral T cell homeostasis results from a balance between factors promoting survival and those that trigger deletion of Ag-reactive cells. The cytokine IL-2 promotes T cell survival whereas reactive oxygen species (ROS) sensitize T cells to apoptosis. Two pathways of activated T cell apoptosis-one triggered by Fas ligand and the other by cytokine deprivation-depend on ROS, with the latter also regulated by members of the Bcl-2 family. Notch family proteins regulate several cell-fate decisions in metazoans. Ectopic expression of the Notch1 intracellular domain (NICD) in T cells inhibits Fas-induced apoptosis. The underlying mechanism is not known and the role, if any, of Notch in regulating apoptosis triggered by cytokine deprivation or neglect has not been examined. In this study, we use a Notch1/Fc chimera; a blocking Ab to Notch1 and chemical inhibitors of gamma-secretase to investigate the role of Notch signaling in activated T cells of murine origin. We show that perturbing Notch signaling in activated CD4(+)/CD8(+) T cells maintained in IL-2 results in the accumulation of ROS, reduced Akt/protein kinase B activity, and expression of the antiapoptotic protein Bcl-x(L), culminating in apoptosis. A broad-spectrum redox scavenger inhibits apoptosis but T cells expressing mutant Fas ligand are sensitive to apoptosis. Activated T cells isolated on the basis of Notch expression (Notch(+)) are enriched for Bcl-x(L) expression and demonstrate reduced susceptibility to apoptosis triggered by neglect or oxidative stress. Furthermore, enforced expression of NICD,protects activated T cells from apoptosis triggered by cytokine deprivation. Taken together, these data implicate Notch1 signaling in the cytokine-dependent survival of activated T cells.