How does metabolism program B cell immunity?

PROJECT OVERVIEW

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 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. The GC reaction is essential for the production of high affinity antibodies and humoral immunity.

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 poorly understood. Importantly, events occurring in the GC reaction lead to the majority of non-Hodgkin’s lymphomas, and are dysfunctional in autoimmune disease. This project aims to identify and understand metabolic programs active in GC B cells, to modify them experimentally using conditional knockout approaches in mouse models, and to target them therapeutically in pre-clinical models.

In this project, you 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. You will have the opportunity to attend the outstanding educational programme provided at the KIR, and to also regularly present your own data in group meetings, seminars, and at international conferences.

KEYWORDS

Metabolism

B cell immunity

Autoimmunity

Lymphoma

Vaccines

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 single cell RNA sequencing. For study of metabolism, you will develop expertise in stable isotope resolved metabolomics, and extracellular flux measurement using the Seahorse platform, and the bioinformatic analysis of these data. Computational biology training will be provided, both within the group and in formal courses.

KEY PUBLICATIONS

Johnstone J, Yazicioglu Y, Clarke AJ. Fuelling B cells: dynamic regulation of B cell metabolism. Current Opinion in Immunology. 2024, 91, 102484

Yazicioglu Y*, Marin E*, Bentkowska K, Andrew H, Johnstone J, Mitchell R, Wong Z, Zec K, Fergusson J, Borsa M, Raza IG, Attar M, Ali M, Kronsteiner B, Furlani I, MacRae J, Devine MJ, Coles M, Buckley C, Dunachie S, Clarke AJ. Asparagine availability controls germinal centre B cell homeostasis. Science Immunology. 2024. 9(102), pp. eadl4613 *Equal authorship.

Yazicioglu Y, Marin E, , Sandhu C, Galiani S, Raza I, Ali M, Kronsteiner B, Compeer E, Attar M, Dunachie S, Dustin ML, Clarke AJ. Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis. Nature Immunology. 2023. 24(6):991-1006

Psarras A, Clarke AJ. A cellular overview of immunometabolism in systemic lupus erythematosus. Oxford Open Immunology. 2023. 4(1): iqad005

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

THEMES

Immunology

Molecular, Cell and Systems Biology

Translational Medicine and Medical Technology

CONTACT INFORMATION OF ALL SUPERVISORS

alexander.clarke@kennedy.ox.ac.uk

michael.dustin@kennedy.ox.ac.uk