Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation
Document Type
Article
Publication Date
9-13-2024
Original Citation
Karginov T,
Ménoret A,
Leclair N,
Harrison A,
Chandiran K,
Suarez-Ramirez J,
Yurieva M,
Karlinsey K,
Wang P,
O'Neill R,
Murphy P,
Adler A,
Cauley L,
Anczuków O,
Zhou B,
Vella A.
Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation Science. 2024;385(6714):eadj1979.
Keywords
JGM, Animals, Humans, Mice, Alternative Splicing, Cell Survival, Conserved Sequence, Exons, Nerve Tissue Proteins, Receptors, Antigen, T-Cell, RNA-Binding Proteins, Serine-Arginine Splicing Factors, T-Lymphocytes
JAX Source
Science. 2024;385(6714):eadj1979.
ISSN
1095-9203
PMID
39265028
DOI
https://doi.org/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.