biostudies-literatureKarginov TANIDDK NIH HHSNIAID NIH HHSAmerican Heart Association-American Stroke AssociationNHLBI NIH HHSNCI NIH HHSNIGMS NIH HHSeadj1979https://www.ebi.ac.uk/biostudies/studies/S-EPMC11697694biostudies-literatureUnknown385(6714)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 <Science (New York, N.Y.)Autoregulated splicing of &lt;i&gt;TRA2&lt;/i&gt;β programs T cell fate in response to antigen-receptor stimulation.PMC11697694R01 GM138541R01 HL172239R01 HL150362P30 CA034196R21 AI139891R01 GM123312F30 HL168980R01 DK121805R01 CA24831723PRE1023195Suarez-Ramirez JEChandiran KVella ATO'Neill RJYurieva MAnczukow OKarlinsey KKarginov TAMurphy PAMenoret ALeclair NKWang PZhou BCauley LSAdler AJHarrison AGfalseAutoregulated splicing of &lt;i&gt;TRA2&lt;/i&gt;β 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. <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 <2024-01-01T00:00:00Z2024 Sep2025-04-04T01:41:25.73Z2025-04-04T01:41:25.73ZS-EPMC116976943926502810.1126/science.adj1979