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Alternative splicing (AS) generates diverse mRNA transcripts from a single gene, enhancing protein variety. This study examines AS during naive CD4 T cell activation, revealing that splicing events precede gene expression changes, evident as early as 6 h post-activation. Splicing alterations primarily impact pathways related to protein metabolism and mRNA processing, while gene expression dynamics affect immune regulatory genes. Notably, splicing isoforms favored soluble ectodomains of surface receptors, including CTLA4. CD8 T cells showed comparable patterns to CD4 cells, primarily differing in immune-related genes. Analysis of T cell-rich tumor samples from melanoma patients showed that AS events prevalent in the CD4 dataset correlated with positive responses to immune checkpoint inhibitors (ICIs). These findings suggest that activation-induced AS in T cells may play an immune regulatory role and be linked to ICI treatment outcomes.