Post-transcriptional control of T-cell development and function by the RNA-binding proteins TIA1 and TIAL1. – TregbyRNA

Effective T cell responses against pathogens rely on a highly dynamic regulation of genetic programs for ample production of cytokines, chemokines, and cytotoxic molecules. The transcriptional networks that control T cell differentiation and activation are well studied. However, genome-wide studies constantly show a very poor correlation between mRNA and protein abundance in T cells, highlighting the importance of post-transcriptional regulatory mechanisms for timely gene expression.
Our preliminary data show that post-transcriptional gene regulation by the RNA binding proteins TIA1 and TIAL1 play fundamental roles in T-cell development and activation, likely by controlling the strength of the TCR signal. Our hypothesis is that TIA1 and TIAL1 are part of a post-transcriptional regulatory program that shapes the T- cell transcriptome during development, differentiation and activation of T cells for mounting effective immune responses. TIA1 and TIAL1 bind to U-rich elements present in introns and 3’UTRs to modulate both mRNA splicing and translation into protein. In this project, we will combine the use of conditional knock out mouse models and in-vivo analysis of protein:RNA interactions to identify the key mRNAs and genetic programs controlled by TIA1 and TIAL1 during T cell development and activation, as well as the functional consequences of T-cell specific deletion of these proteins in different models of disease.
T-cell immunotherapy is now implemented as a reference treatment against several autoimmune disorders and cancer, but its effectiveness is reduced due to central and peripheral immune tolerance as well as from disease associated immune suppression. Therefore, understanding further the basic molecular mechanisms involved in T cell activation and function may identify novel RNA-mediated strategies for therapeutic intervention.