The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes
The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes
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DOI：
10.4049/jimmunol.1800602
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发表时间：
2019-01-15
影响因子：
4.4
通讯作者：
Fruman, David A.
中科院分区：
文献类型：
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作者：
Chiu, Honyin;Jackson, Leandra V.;Fruman, David A.
在适应性免疫应答期间，活化的成熟B细胞产生分泌Ab的浆细胞以对抗感染。B细胞经历Ab类别转换以产生具有不同效应子功能的不同类别的Ab。在此过程中，雷帕霉素（mTOR）信号通路的哺乳动物/机械靶标被激活，并且破坏B细胞中的mTOR复合物1（mTORC 1）会通过一种知之甚少的机制损害类别转换。特别是，目前还不清楚哪些mTORC 1下游底物控制这一过程。在这项研究中，我们使用了一种体外小鼠模型，其中mTORC 1抑制剂雷帕霉素，当加入后，B细胞已致力于分裂，抑制类转换，同时保持增殖。mTORC 1底物的研究揭示了真核翻译起始因子4 E（eIF 4 E）和eIF 4 E结合蛋白在类别转换中的作用。从机制上讲，我们表明，eIF 4 E与eIF 4G结合的遗传或药理学破坏减少了帽依赖性翻译，这特别影响了活化诱导的胞苷脱氨酶蛋白的表达，但不影响Aicda mRNA。这种翻译损伤降低了独立于增殖的Ab类转换。这些结果揭示了mTORC 1和eIF 4 E结合蛋白/eIF 4 E轴在小鼠B细胞中激活诱导的胞苷脱氨酶蛋白表达和Ab类别转换中的先前未描述的作用，表明帽依赖性翻译调节B细胞分化中的关键步骤。
During an adaptive immune response, activated mature B cells give rise to Ab-secreting plasma cells to fight infection. B cells undergo Ab class switching to produce different classes of Abs with varying effector functions. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is activated during this process, and disrupting mTOR complex 1 (mTORC1) in B cells impairs class switching by a poorly understood mechanism. In particular, it is unclear which mTORC1 downstream substrates control this process. In this study, we used an in vitro murine model in which the mTORC1 inhibitor rapamycin, when added after a B cell has committed to divide, suppresses class switching while preserving proliferation. Investigation of mTORC1 substrates revealed a role for eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-binding proteins in class switching. Mechanistically, we show that genetic or pharmacological disruption of eIF4E binding to eIF4G reduced cap-dependent translation, which specifically affected the expression of activation-induced cytidine deaminase protein but not Aicda mRNA. This translational impairment decreased Ab class switching independently of proliferation. These results uncover a previously undescribed role for mTORC1 and the eIF4E-binding proteins/eIF4E axis in activation-induced cytidine deaminase protein expression and Ab class switching in mouse B cells, suggesting that cap-dependent translation regulates key steps in B cell differentiation.