Defining the nature of plasma cell development in germinal centres.

Antibodies are soluble proteins of the immune system that specifically bind to foreign microbial antigens to neutralise their functions and/or mark them for destruction. The elicitation of pathogen-specific antibody responses is considered to be the main basis for the protection provided by vaccines. Remarkably, our immune systems can generate high-affinity (strong-binding) antibodies that are specific for almost any protein or protein-associated entity encountered, which is accomplished by modifying and evolving less specific (weaker) antibodies present within naïve B cell repertoires. At this stage, B cells express antibodies as membrane receptors (B cell receptors, BCRs) that are highly sensitive to recognising antigenic ligands for which they have very minimal binding strength, thereby facilitating B cell activation. Activated B cells enter germinal centres (GCs), specialised structures that form within secondary lymphoid tissues (e.g. lymph nodes) during immune responses. Here, B cells engage in a remarkable process known as antibody affinity maturation that involves rapid proliferation couple with random mutagenesis of their antibody-encoding genes. This generates panels of somatic variant GC B cells with subtly different BCRs. Most of these variants undergo apoptosis; however, occasionally, mutations cause B cells to bind their target more strongly. The presence of such improvements is detected via a “selection” process that causes cells with enhanced antibodies to being preferentially targeted for survival and further proliferative expansion. This process may continue for weeks or even months, leading to incremental improvements in antibody binding strength and enhanced protective function. However, GC B cells do not themselves secrete antibodies, they expressed only as BCRs at this stage; therefore, they must develop into antibody-secreting plasma cells (PCs) through rare differentiation events before they contribute directly to immunity. Despite the fundamental importance of this process – it establishes antibody-mediated immunity – we know very little about the events leading GC B cells to undergo PC differentiation. Notably, it is not yet clear whether GC B cells are actively selected to differentiate directly into PCs or whether instead they develop as a secondary product of clonal expansion, with some daughter cells adopting this fate. These major knowledge gaps limit our ability to design vaccines that trigger the formation of higher numbers of affinity-matured plasma cells, and thereby induce higher titres of high-quality antibodies, and/or to generate drugs for inhibiting antibody synthesis in autoimmune and inflammatory settings. We propose developing new cutting-edge experimental tools that enable us to elucidate the events responsible for triggering PC differentiation in GCs – thereby revealing the processes and mechanisms involved. Therefore, we will answer a major question in adaptive immunity and advance the BBSRC strategic objectives of learning the rules of life and promoting scientific innovation in the UK.