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
{"title":"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","authors":"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","doi":"10.1126/science.adj1979","DOIUrl":null,"url":null,"abstract":"<div >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. <i>TRA2</i>β<i>-</i>PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. <i>Tra2</i>β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, <i>Tra2</i>β-PE reinclusion allowed T cell survival. Finally, we found that <i>TRA2</i>β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that <i>TRA2</i>β<i>-</i>PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation\",\"authors\":\"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\",\"doi\":\"10.1126/science.adj1979\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >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. <i>TRA2</i>β<i>-</i>PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. <i>Tra2</i>β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, <i>Tra2</i>β-PE reinclusion allowed T cell survival. Finally, we found that <i>TRA2</i>β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that <i>TRA2</i>β<i>-</i>PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.</div>\",\"PeriodicalId\":21678,\"journal\":{\"name\":\"Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":44.7000,\"publicationDate\":\"2024-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/science.adj1979\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/science.adj1979","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation
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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