2. Academic Validation
  3. Autoregulated splicing of TRA2 β programs T cell fate in response to antigen-receptor stimulation

Autoregulated splicing of TRA2 β programs T cell fate in response to antigen-receptor stimulation

  • Science. 2024 Sep 13;385(6714):eadj1979. doi: 10.1126/science.adj1979.
Timofey A Karginov 1,  Antoine Ménoret 1,  Nathan K Leclair 2 3,  Andrew G Harrison 1,  Karthik Chandiran 1,  Jenny E Suarez-Ramirez 1,  Marina Yurieva 3,  Keaton Karlinsey 1,  Penghua Wang 1,  Rachel J O'Neill 2 4 5,  Patrick A Murphy 6,  Adam J Adler 1,  Linda S Cauley 1,  Olga Anczuków 2 4 5,  Beiyan Zhou 1 5,  Anthony T Vella 1
Affiliations

Affiliations

  • 1 Department of Immunology, School of Medicine, University of Connecticut, UConn Health, Farmington, CT 06030, USA.
  • 2 Department of Genetics and Genome Sciences, School of Medicine, University of Connecticut, UConn Health, Farmington, CT 06030, USA.
  • 3 The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
  • 4 Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
  • 5 Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA.
  • 6 Center for Vascular Biology, School of Medicine, University of Connecticut, UConn Health, Farmington, CT 06030, USA.
PMID: 39265028 DOI: 10.1126/science.adj1979
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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