Cytokine and glucose control of protein turnover in CD8 T cells

CD8 cytotoxic T-lymphocytes mediate anti-viral and anti-tumour immune responses. Their differentiation to effector cells is driven by antigen receptors, co-stimulatory molecules and cytokines. In this context, immune activated T cells control expression of cytokine receptors, so the function of CD8 T cell populations can be shaped by distinct cytokines. Key cytokines for CD8 T cells include IL2, IL4, IL7, IL15, interferons, IL12, and the alarmins IL18 and IL33. There has been extensive work on the positive signals controlling expression of cytokine and costimulatory receptors, but less is known about how receptors are degraded at different stages of T cell activation. This project uses high resolution mass spectrometry and flow cytometry to explore these questions and determine the half-lives of key receptors. Proteome remodelling in CD8 T cells is dependent on selective pathways of protein degradation mediated by the ubiquitin-proteosome system and nutrient sensing pathways of autophagy. This project will also explore the relative contribution of these pathways in controlling the repertoire of cytokine receptors expressed by CD8 T cells.

Another trait of CD8 cytotoxic T cells is expression of high levels of glucose transporters. This project explores the importance of glucose availability on key cellular responses in cytotoxic T cells, using high resolution mass spectrometry to understand how glucose availability impacts the proteome and controls protein synthesis and degradation to direct cytotoxic T cell function. Known glucose regulated pathways include those of glucose-sensing serine threonine kinases like AMPK activated protein kinase and mammalian target of rapamycin complex 1. Glucose also fuels production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a substrate for O-GlcNAc glycosyltransferase. The thesis will explore the relative contribution of these different glucose regulated signalling pathways to the control of cytotoxic T cell proteomes.