System level understanding of protein degradation pathways in T lymphocytes (360G-Wellcome-227383_Z_23_Z)

The ability of T-lymphocytes to rapidly activate following infection and to curtail effector function following pathogen clearance is fundamental for adaptive immunity. CD8-T-cells, essential for immune responses to viruses and tumours, have highly dynamic pathways of selective protein degradation that drive rapid remodelling of their proteomes in response to pathogens, cytokines, and environmental signals. This is a fundamental mechanism that allows rapid reprogramming for acquisition of effector function or return to quiescence. Pathways important for protein degradation in T-cells include autophagy and the ubiquitin-proteosome system controlled by E3 ubiquitin ligases. However, there are substantial knowledge gaps in our understanding of the molecular mechanisms that control the selectivity of T-cell protein degradation. We will exploit mass spectrometry, chemical biology, and genetic engineering to systematically uncover key regulators of protein degradation in CD8-T-cells in response to changes in their immune and nutrient environment. This project will identify control switches for autophagy in T-cells and deliver a systems level identification of active E3 ligases and their substrates in naïve, effector and memory CD8-T-cell populations. It will transform understanding of how T-cells control exit and entry to quiescence and pinpoint molecules that can be targeted for therapeutic immune interventions to treat autoimmunity and cancer.