Cell intrinsic regulation of B cell activation: Metabolic reprogramming and mitochondrial remodelling

B cells are fundamental components of the adaptive immune system. B-cell activation leads to the formation of effector (plasma cells) and memory (memory B cells) compartments in vivo, which together provide a potent line of defense against pathogenic infections through the production of highly specific antibodies. At the cellular level, B-cell activation triggers the rapid reorganization of the cytoskeleton. It is now recognized that the dynamic remodeling of actin and microtubules is extremely important for B cells in aspects such as receptor signalling, cell motility, as well as intracellular trafficking of membrane compartments. B-cell activation in the longer-term triggers metabolic reprogramming and remodeling of many other intracellular organelles that are required to support increased cell growth, proliferation and differentiation. However, despite previous studies have shed light into the many characteristics of B cell activation and differentiation, our understanding on how B-cell activation and fate decision is coordinated is still incomplete. To address these questions, I set out to investigate firstly the mechanism of cytoskeleton regulation and its role on B-cell activation. This involved the study on the RhoGTPase RhoF and vimentin that were largely uncharacterised in B cells. RhoF- and vimentin-deficient mouse models were used in these contexts combined with techniques including super-resolution light microscopy and electron microscopy. The results obtained suggest that while RhoF does not seem to play a major role in B-cell development and function, the dynamic reorganisation of vimentin is critical for B-cell activation. Loss of vimentin in B cells also affected intracellular trafficking, antigen presentation and in vivo antibody responses. Next, I went on to study the role of metabolic reprogramming on B-cell fate decision using the PKC-deficient model. Despite this topic has been a recent hotspot in the field of T cells, it has so far not been extensively studied in B cells. Combining advanced sequencing and detailed metabolomics analysis, I found that while PKC played multiple roles in B cell function, it is specifically required to initiate an mTORC1-dependent metabolic program to promote plasma cell differentiation. Accordingly, the loss of PKC rendered activated B cells unable to sustain this metabolic program, and as a result favouring differentiation to memory cells. All together, these results provide mechanistic insights into B-cell differentiation and highlight the central role of metabolic reprogramming on fate decision in B cells