The Interconnected Mechanisms of Feedback regulation in CD8 T cells.

CD8 T cell activation sets in motion waves of gene expression accompanied by metabolic changes that promote proliferation and alternative differentiation fates. The ZFP36-family of RNA binding proteins (RBP) regulate this by limiting the tempo of differentiation and potency of CTL. Through interactions with the multiprotein CCR4NOT complex ZFP36-family bound mRNAs are translationally repressed and degraded. This complex and its regulation remains uncharacterised in mature T cells and we propose it acts in activated T cells as a regulatory hub to interconnect and coordinate epigenetic, transcriptional and metabolic reprogramming. We will address how the components of this complex are regulated by TCR and costimulatory signals and their role in negative feedback and inhibitory receptor signalling. We will establish how RBP affect the formation and function of memory cells and test the hypothesis that they promote T cell exhaustion. By developing tools and approaches to define the dynamics of protein and RNA interactions, coupled with analysis of mRNA fate, we will distinguish how target transcripts are regulated. Working in a largely unexplored field these studies will reveal new functions of RBP in metabolism, epigenetic remodelling and RNA localization/trafficking providing insight into a deeper layer of molecular regulation of the immune system.