Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-09-13 DOI:10.1126/science.adj1979

Timofey A. Karginov, Antoine Ménoret, Nathan K. Leclair, Andrew G. Harrison, Karthik Chandiran, Jenny E. Suarez-Ramirez, Marina Yurieva, Keaton Karlinsey, Penghua Wang, Rachel J. O’Neill, Patrick A. Murphy, Adam J. Adler, Linda S. Cauley, Olga Anczuków, Beiyan Zhou, Anthony T. Vella

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Abstract

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. TRA2β-PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2β-PE reinclusion allowed T cell survival. Finally, we found that TRA2β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2β-PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.

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TRA2β 的自动调节剪接可在抗原受体刺激下对 T 细胞的命运进行调控

T细胞受体（TCR）对多肽-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。在这项研究中，我们发现了一种 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 中一个进化超保守的毒外显子（PE）引导 TCR 信号转录本的替代剪接。在癌症和感染期间出现的 TRA2β-PE 剪接是 TCR 诱导的效应 T 细胞扩增和功能所必需的。跳过TRA2β-PE可提高TCR的敏感性，从而增强T细胞对抗原的反应。随着抗原水平的降低，Tra2β-PE 的重新整合使 T 细胞得以存活。最后，我们发现 TRA2β-PE 首次出现在有颌脊椎动物的基因组中，这些脊椎动物能够进行 TCR 基因重排。我们认为，TRA2β-PE的剪接是TCR敏感性的看门人，决定着T细胞的命运。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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