Autoregulated splicing of <i>TRA2</i>β programs T cell fate in response to antigen-receptor stimulation.

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. <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.