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
  • 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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