On Friday 15 October, Imran Sayal defends her PhD thesis "Studies on the development and nature of T-bet expressing Bcells in humans and mice".
Time:13:00
Place: Bldg. 303A, aud. 41 & Zoom: https://dtudk.zoom.us/meeting/register/u5AkcuivrTsvHNV5ecKdDAm_5-xuY7HhpbXr
Please be aware that the PhD defence may be recorded - This will also be informed at the beginning of the PhD defence.
Principal supervisor: Associate Professor Vasileios Bekiaris
Co-supervisor: Associate Professor Bengt Lindbom
Examiners:
Professor Peter Heegaard, DTU Health Tech
Professor Kai-Michael Toellner, University of Birmingham Medical School
Assistant Professor Søren Egedal Degn, Aarhus University
Chairperson at defence:
Professor William Agace, DTU Health Tech
Abstract:
B cells are critical for our ability to protect ourselves against infectious diseases. The most important protective function of B cells is secretion of antibodies, which for example can neutralize viruses or mediate killing of bacteria, but B cell possess other immune functions as well. When these responses are directed against self, due to disruptions in mechanisms regulating B cell activation and function, autoimmune conditions might manifest. During recent years a subset of B cells expressing a protein called T-bet has been discovered. These T-bet expressing B cells have become a focus since they have been shown to have critical roles in both protection against viruses and in development of autoimmune diseases. In this study, we have investigated the phenotype and heterogeneity of T-bet expressing B cells in both mice and humans, and studied molecular mechanisms leading to their generation.
Our studies of B cells in mice show that T-bet is preferentially expressed in subsets of activated B cells. Furthermore, previous studies have shown that a specific subset of T-bet expressing B cells accumulate with age and we show that this accumulation is lost in the absence of help from activated T helper cells. We have also studied the TLR7 ligand R848 and IFN-γ, two molecular pathways previously implicated in the generation of T-bet expressing B cells and in autoimmune disease. We have found that the most critical factor for the generation of these cells is IFN-γ. R848 instead has a strong effect on B cell expansion. Interestingly, we found that IFN-γ is counteracting this R848-induced B cell expansion and we also propose a mechanism for this effect through a known death receptor called Fas. Lastly, we show that IFN-γ is not dependent on T-bet expression in the B cells to exert these effects.
Antibody isotype and subclass to a large extent dictate the functional properties of the antibodies produced by B cells. We have therefore studied T-bet expression in relation to the antibody isotype and subclass expressed by B cell in human peripheral blood. We focused primarily on the two IgA subclasses, which are mostly generated during responses in mucosal tissues, such as the intestinal mucosa. Our results show that T-bet is expressed in memory B cells producing the IgA1 subclass, whereas memory B cells producing IgA2 lack T-bet expression. When we tried to induce concomitant IgA1 and T-bet expression in B cells activated in vitro, we found that cells producing both proteins cannot be generated in the presence of factors known to regulate induction of IgA in the intestinal mucosa, indicating that memory B cells with dual T-bet and IgA1 expression in human blood likely have been generated in tissues distinct from the intestinal mucosa.
In summary, our study contributes to the knowledge of T-bet expressing B cells and provided insights for further research with possible implications for autoimmune diseases, anti-viral immunity and function of the IgA producing B cell compartment.