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How does metabolism reprogram the immune system in autoimmunity? (#202002)


About This PhD Project

Project Description

The systems and pathways of cellular metabolism, modified either by the microbiome or cell-intrinsic programs, are critical to almost all aspects of the immune response. An essential function of metabolism is to dynamically respond to the needs of the cell, typically as it encounters a new microenvironment, or is required to rapidly divide, secrete cytokines, or produce antibodies.

One of the most important outstanding questions in the field is how immune cell metabolism actually operates within tissues in life, and how this is altered in autoimmune disease.

The germinal centre reaction is a tightly choreographed process occurring in secondary lymphoid tissue, as B cells refine their antigen specificity through interaction with T follicular helper cells. GC B cells have the highest proliferation rate of any cell in the body, and yet which metabolic programs are activated and are essential for this process is very poorly understood. Importantly, events occurring in the GC reaction lead to the majority of non-Hodgkin’s lymphomas, and are dysfunctional in the disease systemic lupus erythematosus (SLE). SLE is a frequently life-threatening systemic autoimmune disease, for which only one new therapy has been approved in the last 50 years. There is therefore a great unmet need for new therapeutic approaches. This project aims to identify and understand metabolic programs active in GC B cells in health and in autoimmune disease, to modify them experimentally using conditional knockout approaches in mouse models, and to target them therapeutically in pre-clinical models.

In this project, the student will study the metabolic pathways activated during the germinal centre (GC) reaction in health and in autoimmune disease, using cutting edge technologies and methods which allow measurement of metabolism with high in vivo fidelity.

Training opportunities


This project provides a broad training in immunology, with comprehensive coverage of standard and advanced techniques including disease models, advanced flow cytometry, confocal imaging, and measurement of epigenetic modification. For study of metabolism, the student will develop expertise in stable isotope resolved metabolomics, and extracellular flux measurement using the Seahorse platform, and the bioinformatic analysis of these data. We collaborate with the National Physical Laboratory for mass spectrometry imaging (MSI), which the student will have the opportunity of involvement with. We will combine MSI with high dimensional imaging (e.g. CODEX) to comprehensively map metabolism within tissues. The student will also analyse human clinical samples obtained from patients with autoimmune disease.

The student will benefit from being part of a newly established lab, and so can receive as much hands-on senior supervision as required, but will also be co-supervised and integrated with a much larger group for a broad scientific experience. The student will have the opportunity to attend the outstanding educational programme provided at the KIR, and to also regularly present their own data in group meetings, seminars, and at international conferences.

Publications


Müschen, M. (2019). Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation. Nat Rev Immunol, DOI: 10.1038/s41577-019-0154-3

Clarke AJ et al. (2018) B1a B cells require autophagy for metabolic homeostasis and self-renewal. J Exp Med. DOI: 10.1084/jem.20170771

Boothby M and Rickert RC. (2017) Metabolic regulation of the immune humoral response. Immunity DOI: 10.1016/j.immuni.2017.04.009

De Silva NS and Klein U. (2015) Dynamics of B cells in germinal centres. Nat Rev Immunol DOI: 10.1038/nri3804

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