T cell receptor (TCR) sensitivity to peptide–major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2β in mouse and human. TRA2 β - PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2 β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2 β-PE reinclusion allowed T cell survival. Finally, we found that TRA2 β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2 β - PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.

中文翻译：

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TRA2 β 的自动调节剪接在抗原受体刺激下对 T 细胞命运进行编程


T 细胞受体 （TCR） 对肽主要组织相容性复合体 （MHC） 的敏感性决定了 T 细胞的命运。TCR 敏感性的经典模型不能完全用转录调控来解释。在这项工作中，我们确定了 TCR 敏感性的转录后调控机制，该机制通过小鼠和人类 RNA 结合蛋白 （RBP） TRA2β 中进化上超保守的毒外显子 （PE） 指导 TCR 信号转录物的选择性剪接。TRA2 β - 在癌症和感染期间看到的 PE 剪接是 TCR 诱导的效应 T 细胞扩增和功能所必需的。Tra2 β-PE 跳跃通过增加 TCR 敏感性增强了 T 细胞对抗原的反应。随着抗原水平的降低，Tra2 β-PE 再纳入允许 T 细胞存活。最后，我们发现 TRA2 β-PE 首先包含在能够 TCR 基因重排的有颌脊椎动物的基因组中。我们提出 TRA2 β - PE 剪接充当 TCR 对形状 T 细胞命运敏感性的守门人。