Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation

• 成果类型: Article
• 署名作者: Karginov, Timofey A.; Menoret, Antoine; Leclair, Nathan K.; Harrison, Andrew G.; Chandiran, Karthik; Suarez-Ramirez, Jenny E.; Yurieva, Marina; Karlinsey, Keaton; Wang, Penghua; O'Neill, Rachel J.; Murphy, Patrick A.; Adler, Adam J.; Cauley, Linda S.; Anczukow, Olga; Zhou, Beiyan; Vella, Anthony T.
• 署名单位: University of Connecticut; University of Connecticut; Jackson Laboratory; University of Connecticut; University of Connecticut; University of Connecticut
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11182
• DOI: 10.1126/science.adj1979
• 发表日期: 2024-09-13
• 页码: 1180-+
• 关键词: ultraconserved elements; cd8; differentiation; transcription; expression; memory; genes

摘要

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) TRA2 beta in mouse and human. TRA2 beta-PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2 beta-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2 beta-PE reinclusion allowed T cell survival. Finally, we found that TRA2 beta-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2 beta-PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.