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How regulatory immunological cues (re)programme cellular metabolism to control effector T cell behaviour and function


Faculty of Biology, Medicine and Health

, Prof R K Grencis Applications accepted all year round Self-Funded PhD Students Only

About the Project

Upon activation a T cell transitions from a state of semi-quiescence to a state of high activity. During the process of activation the T cell therefore needs to up regulate metabolic pathways to acquire the energy and nutrients required to facilitate the behavioural changes associated with its new functional state. If a cell fails to re programme its cellular metabolism this leads to defects in many different key effector functions such as migration, proliferation and cytokine production. Interestingly, it is also becoming clear that different subsets of T cells, such as regulatory T cells, Th1, Th2, Th17 and memory cells all express different metabolic signatures, implying that the nature of cellular metabolism specifies the effector or regulatory immune characteristics of the cell.

The aim of this project is to understand how key regulatory immune pathways rewire CD4+ T cell metabolism to suppress effector characteristics of T cells, dampening tissue-damaging inflammation. To address this aim, highly tractable in vitro assays will be used alongside complex in vivo models of inflammation, including malaria and helminth infections. The project will utilise cutting edge combinations of intravital two photon microscopy, transcriptomics, metabolic flux analyses and flow cytometry. Combined, these approaches will delineate the spectrum of action of key regulatory cytokines on effector T cell function, and will show how specific perturbation of metabolic events dominantly modifies T cell activity.

Training in immunology, microscopy, flow cytometry and systems biology will be provided to fit student’s background and interests. The student will join a team of interdisciplinary researchers who have established all of the experimental techniques required for the project. Dr Couper’s background is in malaria immunology, with a focus on in vivo and in vitro analysis of T cell function. Professor Grencis’s background is in helminth immunology, specifically how Th2 responses develop and are regulated. The core facilities at the University of Manchester will provide significant expertise in imaging, genomic technologies, and bioinfomatics.

The student will use and receive training in microscopy (two-photon and confocal), metabolic flux analyses (Seahorse analyser), transcriptomics and a variety of cutting edge immunological techniques, such as multiparameter flow cytometry. The student will also obtain training in in vivo experimentation.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Biology, Immunology or a related subject. Candidates with experience in immunology or with an interest in T cell biology, imaging of immune cell behaviour/metabolism are encouraged to apply.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

1. The spectrum of T cell metabolism in health and disease. Bantug GR, Galluzzi L, Kroemer G, Hess C. Nat Rev Immunol. 2017 Sep 25. doi: 10.1038/nri.2017.99

2. T cell metabolism drives immunity. Buck MD, O'Sullivan D, Pearce EL. J Exp Med. 2015 Aug 24;212(9):1345-60. doi: 10.1084/jem.20151159.

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