Dr S Ross
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
T lymphocytes are an essential component of the adaptive immune system that defends our bodies from invading pathogens and protects against the growth of abnormal cells. Cytotoxic T lymphocytes (CTLs) are one subset of T lymphocytes that identify and destroy infected or damaged cells. In certain circumstances, CTLs become inhibited and, as a result, diseased cells persist in the body resulting in chronic infections and the growth of cancers.
To eradicate unhealthy cells, CTLs make millions of effector molecules. This requires CTLs to metabolise glucose and glutamine to generate the energy and metabolites that are needed to sustain their differentiation and function. Oxygen plays a critical role in controlling cellular metabolism, but when CTLs infiltrate tissues, they may be subjected to low oxygen levels (hypoxia). We are interested in understanding how hypoxia may impede CTL function. Our data suggest that hypoxia causes extensive metabolic reprogramming in CTLs. Beyond energy generation, this has consequences for the production of metabolic intermediates, including those that act as biosynthetic building blocks and signalling molecules; as yet, it is unclear how these metabolic alterations influence CTLs under low oxygen stress.
This project will explore the metabolic adaptations to hypoxia and test the hypothesis that CTLs become dependent on “alternative” nutrient sources and metabolic pathways to supplement glucose and glutamine metabolism to function during hypoxia. Primary cultures of CTLs will be used to determine if perturbation of these alternative nutrient sources impact on the activities of CTLs in hypoxia. The metabolic fates of the nutrients will be investigated in order to determine if they contribute to energy production, if they are required to synthesise cellular components (e.g. lipids) or if they generate molecules that are used for signalling via protein post translational modifications. Following on, experiments will be designed to determine how the spectrum of events initiated by these metabolic pathways impact on CTL function to control signalling, gene transcription and/or cellular biosynthesis. The studentship will provide opportunities to utilise a variety of techniques including biochemistry, flow cytometry, mass spectrometry and next-generation sequencing. It will generate important insights into how different metabolic pathways support the function of CTLs, and how low oxygen levels may make CTL vulnerable to loss of these alternative nutrients from their environment. The supervisor of this project is experienced in characterising signalling pathways that control T lymphocyte function1,2 and the project will complement a research program in the lab that aims to create a molecular understanding of the role of oxygen in regulating T lymphocyte immune responses to uncover new approaches for improving the efficacy of immunotherapies.
In addition to offering training in a comprehensive range of techniques, the project will include opportunities to collaborate with experts in mass spectrometry, genomic technologies and bioinformatics within the Babraham Institute to develop practical and analytical skills and experience for the foundation of a research career. This project would suit an enthusiastic and motivated student interested in combining experimental and “big data” analysis training in order to understand the biochemistry of the immune system.
References
1. Ross, S. H. et al. Phosphoproteomic Analyses of Interleukin 2 Signaling Reveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8(+) T Cells. Immunity 45, 685–700 (2016).
2. Rollings, C. M., Sinclair, L. V., Brady, H. J. M., Cantrell, D. A. & Ross, S. H. Interleukin-2 shapes the cytotoxic T cell proteome and immune environment-sensing programs. Sci Signal 11, eaap8112 (2018).