Functions of human memory B cells and the diversity of the memory B cell population

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Memory B cells (MBC) play a central role in humoral immunity. Distinct subpopulations of human MBC have been identified, including class-switched, IgM+IgD+CD27+, and IgM-only MBC, but their specific features and functions are poorly understood. We generated gene expression profiles of naïve B cells and the three main subsets of MBC and revealed hundreds of differentially expressed genes and different expression of functionally linked genesets. We aim to validate these data and perform functional studies for particular genes to test the hypothesis that the distinct MBC subsets have different features and fulfil specific and distinct functions. Further preparatory work revealed that class-switched and IgM+IgD+CD27+ MBC can derive from common germinal centre B cell clones. However, there is still no comprehensive knowledge about the complexity and intraclonal diversity of the MBC population, and whether distinct MBC subsets derive from the same or distinct immune responses. Therefore, the second main aim of this application is to clarify these issues by next generation sequencing of immunoglobulin V region genes from five subsets of human MBC. In a third part, we will isolate antigen-specific memory B cells by cell sorting and determine their clonal complexity and the existence of antigen-specific clonally related IgG+ and IgM+ MBC. Together, these studies will give essential novel insights into MBC generation and function in the human, and also set a basis for a better understanding of a disregulated humoral immune system in diseases.