Dissecting the regulation of cell fate decisions in humoral immune responses

Cell fate decisions made by B cells upon activation determine the outcome of responses to pathogens and vaccines. In this thesis, we first examined the cell fate decisions that take place early upon B cell activation and identified the transcription factor Bhlhe40 as a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction by limiting TFH cell proliferation and restricting early GCBC differentiation while not interfering with EMBC and EPC differentiation. Bhlhe40-deficient mice with age developed B cell lymphoma, highlighting the role of this transcription factor as a negative regulator of the GC reaction.

Subsequently, using single-cell RNA sequencing and fate-mapping approaches, we revealed that upon activation, a surprisingly large fraction of B cells rapidly exits the cell cycle, giving rise to non-GC-derived EMBCs that make a prominent contribution to the overall MBC pool, a process that was evolutionary conserved between rodents and primates. This phenomenon was controlled by the rapid decline of antigen availability, and the provision of antigen excess precluded the cell cycle exit and induced a new wave of EPCs, indicating that a reservoir of EMBCs may enable the rapid readjustment of the immune response when failure to contain a threat is manifested by increased antigen availability.

Next, focusing on MBC differentiation, we investigated the origin and function of an MBC population that resembles phenotypically MZB cells. We revealed that antigen-specific MZ-memory B cells (MZ-MBCs) generated upon immunization can be longer-lived relative to follicular memory B cells (FO-MBCs) residing in the spleen or lymph nodes. These MBCs, due to their strategic positioning in the MZ of the spleen, could provide the first line of defense in secondary immune responses to bloodborne challenges.

Overall, the data presented in this thesis reveal complex dynamics regarding early B cell activation and memory formation, with findings that can be relevant for future vaccine design.

List of scientific papers

I. René Rauschmeier*, Annika Reinhardt*, Charlotte Gustafsson, Vassilis Glaros, Artem V. Artemov, Josefine Dunst, Reshma Taneja, Igor Adameyko, Robert Månsson, Meinrad Busslinger, and Taras Kreslavsky.

Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis.

Journal of Experimental Medicine. 2022 Feb 7;219(2):e20211406. *Equal contribution. https://doi.org/10.1084/jem.20211406

II. Vassilis Glaros*, René Rauschmeier*, Artem V. Artemov*, Annika Reinhardt*, Sebastian Ols*, Aikaterini Emmanouilidi, Charlotte Gustafsson, Yuanyuan You, Claudio Mirabello, Asa K. Björklund, Laurent Perez, Neil P. King, Robert Månsson, Davide Angeletti, Karin Loré, Igor Adameyko, Meinrad Busslinger, and Taras Kreslavsky.

Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response.

Immunity. 2021 Sep 14;54(9):2005-2023.e10. * Equal contribution. https://doi.org/10.1016/j.immuni.2021.08.017

III. Vassilis Glaros, Nimmy Francis, Gretchen Harms Pritchard, Julia Hauenstein, Kewei Ye, Gustavo Monasterio, William R. Schief, Eduardo J. Villablanca, Stephan P. Rosshart, Jonathan M. Coquet, Robert Månsson, Marion Pepper, E. Ashley Moseman and Taras Kreslavsky.

The marginal zone B cell molecular program is a niche-induced state associated with long-term persistence of B cell memory.

[Manuscript].