Metabolic microenvironments in humoral immunity

Objective

Immune responses occur in often highly compartmentalised tissue microenvironments, which in turn define local metabolic conditions. In the architecture of lymphoid tissue, very little is known about cellular metabolic interactions, or how immune cells adapt their metabolism in response to a changing environment. The humoral immune response is essential for normal immunity, and its centrepiece is the germinal centre (GC) reaction, which allows the generation of high-affinity antibodies and B cell memory. The GC is tightly spatially organised in lymphoid tissue, but how this microenvironment shapes the metabolism of GC B cells is unknown. In this project, we will explore two fundamental questions in B cell metabolism. GC B cells, despite dividing at the highest rate of any cell, have a highly distinct metabolism dependent on OxPhos. Yet, the processes which maintain this are poorly understood. We will examine the role of dynamic mitochondrial morphology in GC homeostasis, using comprehensive metabolic and immune phenotyping across multiple genetic models. In the second aim, we will explore the effect and sensing of environmental metabolites on GC function, and how stromal cells actively regulate their metabolic microenvironment, in both health and the autoimmune disease systemic lupus erythematosus.