Regulation of antigen specific B and CD4 T cell responses

Regulation of human T cell-dependent B cell differentiation and IgG formation

IgG secreting B cells are essential for immunity against pathogens, but also lead to pathology when they are formed against self-antigens in autoimmunity or against allo-determinants upon transfusion of blood cells (alloimmunization). In close collaboration with the group of Anja ten Brinke, we investigate T cell-dependent B cell responses to gain understanding of how B cells differentiate into antibody secreting cells and memory B cells. Specifically, we focus on T cell-dependent B cell responses, since T cells are essential for formation of affinity matured and class-switched protective and pathogenic (IgG) antibodies. Elucidation of the extrafollicular and germinal center pathways and the B cell stages that precede formation of antibody secreting cells and memory B cells would allow therapeutic interventions that either boost or block specific ongoing B cell responses, without affecting other B cells. Current therapies against unwanted B cell responses still affect the total B cel compartment, which can lead to side effects and impact protective immunity. Identification of markers and regulators of B cell differentiation is much desired to prevent alloantibody formation (eg RhD in pregnant women, RBC and platelet transfusions), to intervene against autoantibodies (MS/vasculitis/pemphigus/SLE/RA) or to enhance desired IgG-formation (hyperimmunisation/vaccination).

We tackle our research aims by combining 1) ex vivo analyses of ongoing specific B cell responses in human, with 2) in vitro B cell differentiation studies in established B-T cell models and 3) multi-omics in silico analyses of single specific B cells. We investigate how B-CD4 T cell interactions lead to coregulation of the specific B and T cell responses, with a specific focus on regulation by antigen, costimulation and cytokines. We investigate how the context of an antigen affects its B cell receptor-mediated uptake in B cells and B cell differentiation. We recently identified novel stages of extrafollicular and germinal center-derived B cell differentiation after antigen exposure in vivo. Using combined proteomics, single cell transcriptomics and BCR clonal repertoire analysis over time after antigen exposure, we identified precursors of antibody secreting cells and memory B cells. It brings us closer to the decision point that steers to either memory B cell or antibody secreting cell differentiation. Studies with repeated SARS-CoV-2 vaccination allowed recent identification of memory B cell subsets that show distinct dynamics of reactivation. 

As follicular T helper (Tfh) cells are crucial for B cell help, we also investigate how Tfh formation and their effector functions are regulated. Knowledge of factors that control human Tfh plasticity is still limited. Our recent experiments showed that human antigen-specific B cells strongly drive Tfh priming and reactivation, in contrast to DCs that induce Th1 polarization. B cells thus seem to direct CD4 T cell differentiation towards optimal help for antibody responses. B cell-depleting therapies demonstrated that B cells also regulate CD4 T cell responses in general through unknown mechanisms. We identified two pathways via which B cells regulate CD4 effector T cell formation and control the balance between central and effector memory CD4 T cell formation. We are currently unraveling these regulatory pathways in detail.

Finally, as analyses of regulatory networks is of crucial importance to tackle our research questions well, we have a strong focus to embed multi-omics-focused bio-informatics and systems biology into our research.