A Posttranscriptional Pathway of CD40 Ligand mRNA Stability Is Required for the Development of an Optimal Humoral Immune Response.
A Posttranscriptional Pathway of CD40 Ligand mRNA Stability Is Required for the Development of an Optimal Humoral Immune Response.
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CD40配体mRNA稳定性的转录后途径是发展最佳体液免疫应答所必需的。
DOI：
10.4049/jimmunol.2001074
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发表时间：
2021-06-01
期刊：
影响因子：
--
通讯作者：
Covey LR
中科院分区：
文献类型：
--
作者：
Narayanan B;Prado de Maio D;La Porta J;Voskoboynik Y;Ganapathi U;Xie P;Covey LR
CD40L mRNA的稳定性依赖于一条激活诱导的途径，该途径是由含有多功能RNA结合蛋白多嘧啶结合蛋白1(PTBP1)的RNA结合复合体与转录本的3‘非翻译区结合所介导的。为了了解在T依赖(TD)反应中调节的CD40L表达与不同表达要求之间的关系，我们设计了一只缺乏CD40L稳定元件(CD40L∆5)的小鼠，并研究了这种突变如何改变体液免疫的多个方面。我们发现，CD40L∆5小鼠在60%的WT水平上表达CD40L，并且表达降低对应于TD抗体水平显著降低，生发中心(GC)B细胞丢失和GC结构紊乱。CD40L∆5小鼠B细胞基因表达分析显示，与细胞周期和DNA复制相关的基因显著下调，与细胞凋亡相关的基因显著上调。重要的是，尽管表达高亲和力抗体的细胞数量大大减少，但体细胞超突变相对不受影响。重要的是，观察到浆母细胞和早期记忆B前体细胞占GL7+B细胞总数的百分比的显著损失，表明导致GC后亚群发展的分化信号高度依赖于取决于mRNA稳定性的CD40L阈值水平。因此，调节的mRNA稳定性在体液免疫的优化中发挥着不可或缺的作用，因为它允许CD40L在CD4T细胞上的动态水平表达，从而导致前GC和GC B细胞的增殖和分化为功能亚群。
CD40L mRNA stability is dependent on an activation-induced pathway that is mediated by the binding of RNA binding complexes containing the multifunctional RNA binding protein, polypyrimidine tract-binding protein 1 (PTBP1) to a 3’ untranslated region of the transcript. To understand the relationship between regulated CD40L expression and the requirement for variegated expression during a T-dependent (TD) response, we engineered a mouse lacking the CD40L stability element (CD40L∆5) and asked how this mutation altered multiple aspects of the humoral immunity. We found that CD40L∆5 mice expressed CD40L at 60% WT levels and lowered expression corresponded to significantly decreased levels of TD antibodies, loss of germinal center (GC) B cells and a disorganized GC structure. Gene expression analysis of B cells from CD40L∆5 mice revealed that genes associated with cell cycle and DNA replication were significantly downregulated and genes linked to apoptosis highly upregulated. Importantly, somatic hypermutation was relatively unaffected although the number of cells expressing high affinity antibodies was greatly reduced. Importantly, a significant loss of plasmablasts and early memory B precursors as a percentage of total GL7+ B cells was observed indicating that differentiation cues leading to the development of post-GC subsets was highly dependent on a threshold level of CD40L dependent on mRNA stability. Thus, regulated mRNA stability plays an integral role in the optimization of humoral immunity by allowing for a dynamic level of CD40L expression on CD4 T cells that results in the proliferation and differentiation of pre-GC and GC B cells into functional subsets.
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影响因子：
56.9
作者：
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通讯作者：
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