研究人员发现了一种T细胞受体（TCR）敏感性的转录后调控机制，它通过小鼠和人类中RNA结合蛋白（RBP）TRA2β中的一个演化超保守毒性外显子（PE）指导TCR信号转导转录本的可变剪接。TRA2β-PE剪接在癌症和感染期间被观察到，并且是TCR诱导的效应T细胞扩增和功能所必需的。
跳过Tra2β-PE可通过提高TCR敏感性增强T细胞对抗原的反应。当抗原水平下降时，重新包含Tra2β-PE允许T细胞存活。最后，研究人员发现TRA2β-PE首次出现在具有TCR基因重排能力的有颌脊椎动物的基因组中。研究人员提出TRA2β-PE剪接作为TCR敏感性的守门人，从而塑造T细胞命运。
据悉，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。经典的TCR敏感性模型无法完全用转录调控来解释。
附：英文原文
Title: Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation
Author: 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
Issue&Volume: 2024-09-13
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.
DOI: adj1979
Source: https://www.science.org/doi/10.1126/science.adj1979