TY - JOUR TI - Alternative splicing of apoptosis genes promotes human T cell survival AU - Blake, Davia AU - Radens, Caleb M AU - Ferretti, Max B AU - Gazzara, Matthew R AU - Lynch, Kristen W A2 - Black, Douglas L A2 - Taniguchi, Tadatsugu VL - 11 PY - 2022 DA - 2022/10/20 SP - e80953 C1 - eLife 2022;11:e80953 DO - 10.7554/eLife.80953 UR - https://doi.org/10.7554/eLife.80953 AB - Alternative splicing occurs in the vast majority of human genes, giving rise to distinct mRNA and protein isoforms. We, and others, have previously identified hundreds of genes that change their isoform expression upon T cell activation via alternative splicing; however, how these changes link activation input with functional output remains largely unknown. Here, we investigate how costimulation of T cells through the CD28 receptor impacts alternative splicing in T cells activated through the T cell receptor (TCR, CD3) and find that while CD28 signaling alone has minimal impact on splicing, it enhances the extent of change for up to 20% of TCR-induced alternative splicing events. Interestingly, a set of CD28-enhanced splicing events occur within genes encoding key components of the apoptotic signaling pathway; namely caspase-9, Bax, and Bim. Using both CRISPR-edited cells and antisense oligos to force expression of specific isoforms, we show for all three of these genes that the isoform induced by CD3/CD28 costimulation promotes resistance to apoptosis, and that changes in all three genes together function combinatorially to further promote cell viability. Finally, we show that the JNK signaling pathway, induced downstream of CD3/CD28 costimulation, is required for each of these splicing events, further highlighting their co-regulation. Together, these findings demonstrate that alternative splicing is a key mechanism by which costimulation of CD28 promotes viability of activated T cells. KW - alternative splicing KW - lymphocytes KW - apoptosis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -