The RNA-Binding protein PTBP1 plays a role in the activation of mouse CD8 T cells

Abstract

CD8 T cells play a pivotal role in immune responses against intracellular pathogens, including viruses and bacteria, and in tumour surveillance. After encountering an antigen, CD8 T cells undergo cell growth, clonal expansion, and acquisition of effector functions. These steps are a result of controlled gene expression changes dependent on transcriptional and post- transcriptional mechanisms. These processes are tightly regulated, but little is known about the mechanisms through which these processes are integrated. RNA-binding proteins play a pivotal role in controlling and regulating these processes. Here we show how the RNA-binding protein PTBP1 is dispensable for T cell development but has an essential role in regulating CD8 T cell activation, proliferation, and production of effector molecules. To investigate the roles of PTBP1 in CD8 T cells we generated a mouse model which conditionally deletes Ptbp1 in mature T cells. We found that PTBP1 has an essential role in regulating early events in CD8T cell activation resulting in the production of the effector molecules IL-2 and TNFa. It is also required for optimal proliferation and survival of clonally expanding CD8 T cells. PTBP1 controls a program of Alternative Splicing of many genes. One of these, the catalytic subunit of Calcineurin Ab and Ag may be linked to translocation of c-Fos, NFATc2 and NFATc3 in the nucleus of T cells. These findings reveal a crucial role for PTBP1 in regulating post-transcriptional regulation of genes involved in CD8 T cell activation and effector functions.