The function of oxidative phosphorylation in early B cell development

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Early B-cell development in bone marrow generates the primary B-cell receptor repertoire (BCR) through V(D)J/VJ recombination and proliferation of pre B cells. In previous work, we have described the metabolic changes underlying this differentiation process: We found a relative decrease in glycolysis versus oxidative phosphorylation (OxPhos) in nontransformed pre versus pro B cells. Therefore, we initially suspected that glycolysis was driving pre-B cell expansion. However, we have now investigated the role of oxidative phosphorylation (OxPhos) during early B cell development. To this end, we induced dominant-negative mitochondrial helicase Twinkle (DNT) in pro B cells by mb1Cre-mediated recombination. DNT expression reduces mitochondrial DNA (mtDNA) copy number, and thus OxPhos. Using this system, we demonstrated that DNT expression prevents pre-B cell formation as well as normal IgM heavy chain expression in pro B cells. Consistently, this greatly reduces the number of pre-B cells and mature B cells. We hypothesize several mechanisms that regulate the formation of pre B cells under conditions of greatly reduced OxPhos. The overall goal of this project is therefore to decipher the interplay between metabolism, in particular OxPhos, IgM heavy chain formation in pro-B cells and subsequent pre B and B cell development. We will use a combination of hypothesis-driven and exploratory approaches to address the main question. This project has references to the normal formation of the B cell receptor repertoire, its alteration in aging, malignant transformation of pre-B cells, and for B cell regeneration after B cell depletion.