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. Epub 2024 Sep 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.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Cell Survival
  • Conserved Sequence
  • Exons*
  • Humans
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, Antigen, T-Cell* / metabolism
  • Serine-Arginine Splicing Factors* / genetics
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Nerve Tissue Proteins
  • Receptors, Antigen, T-Cell
  • RNA-Binding Proteins
  • Serine-Arginine Splicing Factors
  • TRA2B protein, human
  • Tra2b protein, mouse