Fine-tuning the germinal centre reaction: understanding the molecular mechanisms for the regulation of B cell responses by TGFß – FiReBird

Germinal centres (GC) are dynamic microenvironments in which, during T cell-dependent responses, mature B cells differentiate into memory B and antibody (Ab)-secreting plasma cells (PC). After antigen (Ag) encounter and interaction with Ag-specific follicular helper T cells (Tfh), B cells undergo 1) affinity maturation of their immunoglobulin (Ig) gene (through somatic hypermutation of the Ag binding site and stringent selection), and 2) class-switch recombination to promote a fitting response. The GC reaction is thus critical for efficient protection against pathogens, but its defective regulation may lead to allergy, lymphomas or autoimmune diseases.

Transforming Growth Factor beta (TGFß) is a known modulator of Ab responses, but so far studies have been unable to reconcile the seemingly contradictory effects of TGFß on B cells. In the gut, we and others, have established the key role of alpha(v)beta8 integrin (avß8) on dendritic cells (DCs) in regulating intestinal T cell responses via activation of TGFß. Indeed, TGFß is secreted in a latent form and must be activated before it can trigger signalling. Importantly, avß8-mediated TGFß activation requires cognate interaction between DCs and T cells and is regulated at the level of ß8 integrin gene expression, av being ubiquitously expressed.

Recently, a new subset of follicular regulatory T cells (TFR) that suppresses the GC reaction has been discovered. Follicular T cells (Tfh and Tfr) are instrumental for the GC reaction but how the B cell-Tfh-Tfr ‘ménage à trois’ controls it remains an open question. In exciting preliminary data, we show that Tfh and Tfr express avß8 integrin. This proposal is based on the novel hypothesis that controlled delivery of active TGFß by avß8 on Tfh/Tfr plays an essential role in fine-tuning the GC reaction. At each contact with Tfh/Tfr, the fate of the recipient B cell will be determined by both accessory signals (co-stimulation, cytokines…) and TGFß delivered in the context of a synapse. Thus, we propose to take an innovative perspective on the GC reaction by focusing on the mechanisms that control TGFß availability through regulation of avß8 expression on follicular T cells, and its involvement in normal and pathological B cell responses. Specifically, we aim at defining the contribution of avß8-mediated activation of TGFß to Ab-mediated host defence and diseases, and to identify ways to modulate avß8 expression in order to control B cell responses.

The strength of this proposal comes from the combination of strategies that will allow a transdisciplinary approach, from epigenetics studies to in vivo validation. The molecular bases of avß8 expression regulation and the role of this process in B cell responses are unknown. Our recent reporter mouse model and new epigenomics approaches render the study of ß8 expression regulation experimentally possible at unprecedented scale. Besides, we obtained exciting preliminary data showing that this process is involved in TD B cell response. Finally, along the way, we will establish the clinical relevance of avß8-mediated regulation of humoral responses.

Therefore, this project should have a strong impact on our knowledge of the regulation of the GC reaction, and by extension on Ab-mediated pathologies. In addition, it will provide important resources for the community, with possible new models for human pathologies where regulation of ß8 expression is targeted. This study also has the potential to uncover unanticipated roles for TGFß and avß8 that simply cannot be proposed a priori through a “classical” hypothesis-driven approach and will thus open new scientific horizons in yet unpredictable ways. Therefore, in the long run, this project will not only give its coordinator the opportunity to strengthen her independence and influence in the field, but will also be essential for developing innovative vaccine and therapeutic strategies targeting infectious diseases and Ab-mediated pathologies.