Department of Immunology, School of Medicine, University of Connecticut, UConn Health, Farmington, CT 06030, USA.
Department of Genetics and Genome Sciences, School of Medicine, University of Connecticut, UConn Health, Farmington, CT 06030, USA.
Science. 2024 Sep 13;385(6714):eadj1979. doi: 10.1126/science.adj1979.
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. βPE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, β-PE reinclusion allowed T cell survival. Finally, we found that β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that βPE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.
T 细胞受体 (TCR) 对肽-主要组织相容性复合物 (MHC) 的敏感性决定了 T 细胞的命运。TCR 敏感性的典型模型不能完全用转录调控来解释。在这项工作中，我们确定了一种 TCR 敏感性的转录后调控机制，该机制通过 RNA 结合蛋白 (RBP) TRA2β 中的一个进化上高度保守的毒(exon) (PE) 指导 TCR 信号转录本的选择性剪接，在小鼠和人类中均如此。在癌症和感染期间观察到的βPE 剪接对于 TCR 诱导的效应 T 细胞扩增和功能是必需的。β-PE 跳过通过增加 TCR 敏感性增强了 T 细胞对抗原的反应。当抗原水平下降时，β-PE 的重新包含允许 T 细胞存活。最后，我们发现β-PE 首先被包含在能够进行 TCR 基因重排的有颌脊椎动物的基因组中。我们提出βPE 剪接作为 TCR 敏感性的守门员，以塑造 T 细胞的命运。
