A new study published in Cell, led by NDM’s Dr Oliver Bannard, Sir Henry Dale Fellow, and Adrien Sprumont, DPhil Student, has used genetic fate-mapping and antibody analysis to Antibodies are soluble proteins that bind specifically to sites on pathogens (called antigens) to neutralise their normal functions (e.g. blocking host cell entry) or to trigger their killing by the immune system. Antibodies are produced by a type of white blood cell called B cells. The generation of antigen-specific antibody responses is a central function of the adaptive immune system that is essential for infection control and long-term immunity.
Over the course of an immune response, the binding affinities of antibodies will improve. This process occurs in germinal centres, which are formed by activated B cells and helper T cells (another type of immune cell) in response to an infection or vaccination. Alongside this role in antibody maturation, germinal centres are also involved in plasma cell development.
Inside germinal centres, B cells improve their antibodies by mutating the genes that encode their antigen-binding regions and undergoing sequential rounds of selection (in the form of directed molecular evolution). However, the B cells in germinal centres do not secrete these antibodies themselves. Instead, germinal centres continuously generate small numbers of plasma cells (through B cell differentiation), which subsequently secrete the affinity-matured antibodies and thereby contribute directly to the effector response against infection. Differentiation of these plasma cells is thought to involve strict selection towards cells producing antibodies with the highest affinity antigen receptors for the specific antigen. However, how this occurs during a real immune response is not well understood.
In this new study by the Bannard Group, researchers used genetic fate-mapping to mark cells actively involved in germinal centres at given points in time in order to capture plasma cells as they emerged from them. They coupled this with analysis of the antibodies produced by these cells, through single B cell antibody cloning, antibody expression and affinity measurement assays, to gain snapshots of the plasma cells generated in germinal cells throughout the response to an infection.
Their results showed that germinal centres actually produce diverse populations of plasma cells expressing antibodies with binding affinities that differ by hundreds, or even multiple thousands, of fold. This included plasma cells with low antibody affinities, which was unexpected.
Prof Bannard said: ‘To understand why germinal centres would have evolved to generate plasma cells with comparatively low antibody affinities, it is important to consider what is important for an antibody to have potent function. While antibody binding strength is certainly an important parameter, potency also critically depends on the site of antigen binding (epitope) and the molecular interactions employed. B cells have no way to “read” whether their antibodies recognize good or bad epitopes, therefore the generation of PC of low antibody affinity may represent an important evolutionary compromise for helping ensure responses are sufficiently broad and include antibodies that may be potent (recognising key sites of pathogen vulnerability) but not of the very highest binding affinity.’