Thesis Niels Verstegen

Summary

The immune response to T cell-dependent antigens relies heavily on the differentiation of B cells into high-affinity memory B cells and antibody-secreting cells (ASC). This process is initiated by the recognition of antigens and repeated interactions between B cells and T follicular helper (Tfh) cells. Tfh cells select B cells based on their ability to present antigens as peptide complexed with major histocompatibility complex II (p:MHCII), resulting in a prolonged interaction between Tfh and B cells, which drives the humoral response. This thesis aims to understand the regulation of Tfh cell and B cell differentiation and function. The research identified the signaling pathway necessary for internalization and presentation of large particles by human B cells. Moreover, the research highlights the plasticity of Tfh cell phenotype, with the ability to co-express multiple cytokines regulated temporally by T cell receptor stimulation. The research also contributed to a better understanding of how the signals delivered by Tfh cells, particularly CD40L and cytokines IL-21 and IL-4, integrate to drive ASC differentiation. By using single-cell RNA sequencing and analysis of B cell differentiation in vitro, a novel ASC-precursor population and in vitro B cell differentiation pathways were identified that accurately recapitulate germinal center B cell reactions and early memory B cell formation. Overall, this thesis provides insights into the intricate interplay between Tfh cells and B cells during the immune response. The findings could aid in developing novel therapeutic strategies for immune-related disorders by providing a better understanding of the regulation of B cell differentiation.