Thesis Peter-Paul Unger

Summary:

Peter-Paul addressed various aspects involved in the generation of human T cell-dependent B cell and antibody responses. Differentiation of naive B cells into IgG- and IgE-secreting plasmablasts and plasma cells, collectively termed antibody-secreting cells (ASCs), depends on antigen internalization and processing and attraction of T follicular helper (TFH) cell signals by activated B cells in secondary lymphoid organs.

In his thesis Peter-Paul showed that B cell receptor-activated NCK-PI3K-RAC1 pathway, but not the CD19 co-receptor complex, is required for actin-mediated internalization of large particles by B cells.

When investigating the TFH cell factors that regulate B cell differentiation, he demonstrated strong and repetitive CD40 co-stimulation and IL-21 is a minimal requirement for strong human naive B cell proliferation followed by efficient differentiation into ASCs. Single-cell RNA sequence analysis and combination with human cell atlas ex vivo data elucidated B cell differentiation trajectories identifying B cell subsets at different stages of differentiation (including germinal center (GC) markers) and potential novel ASC differentiation factors.

Investigation of the IgG4 and IgE B cell responses showed that both responses are relatively short-lived and led to the identification of a potential bottleneck in the naive B cell priming phase for induction of IgG4  cells. This was mediated by IL-4-secreting TFH cells that are needed for IgG4 B cell formation, but also induce reduced chemokine receptor expression needed for good GC reactions.  

Finally, he revealed that in vitro induced IL-10+ B cells do not represent a bona fide regulatory B cell subset, as these cells co-produce pro-inflammatory cytokines and do not have a unique discriminative phenotype and express IL-10 only transiently.

Together, the insights from this thesis may be beneficial for immunomonitoring and therapies targeting B cell/antibody-mediated (auto-) immune diseases.