Alternative Splicing and expression dynamics in T cells

Alternative splicing (AS) is a process that encompasses most of the human genes. A well known AS event occurs in T cells where upon activation the CD45 isoform repertoire changes. The longer isoform in naïve T-cells, CD45RA, shifts to the shorter isoform, CD45RO. This switch in transcriptional expression enables the faster activation of effector and memory T-cells. Another example is SLAMF6 receptor which has a longer canonical isoform that inhibits lymphocyte activation while a shorter isoform augments activation. A more comprehensive understanding of AS in T-cells can help find more key role AS event, which may also have a therapeutic capacity for cancer. We implemented AS analysis tools on three different datasets, naïve and activated CD4 T-cells, CD4 tumor infiltrating cell and on melanoma biopsies. Our analysis showed that the splicing system responded faster to the activation signal than the expression system, and that they focus on different pathways. While both processes regulate the cell cycle pathway, splicing is activated almost immediately, whereas expression changes are noted after 24 hours. While both affect immune pathways, the splicing mechanism affects more prominently the basic functions of the cell such as transcription factors, polymerases, metabolism and splicing factors. Moreover, we noted that main immune related genes undergo AS, such as CTLA4 and FAS. Furthermore, using the CD4 T-cell significant AS events we were able to predict response to immunotherapy treatment of melanoma patients. This analysis has illuminated the inner mechanism of T lymphocytes and the relationship between expression and splicing.