From affinity selection to kinetic selection in Germinal Centre modelling

Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC. To investigate the GC selection bias towards rapid and tight binding, we developed an agent-based model of GC and compared the evolution of founder B cells with initially identical low affinities but with different association/dissociation rates for Ag presented by follicular dendritic cells in three Ag collection mechanisms. We compared an Ag collection mechanism based on association/dissociation rates of B-cell interaction with presented Ag, which includes a probabilistic rupture of bonds between the B-cell and Ag (Scenario-1) with a reference scenario based on an affinity-based Ag collection mechanism (Scenario-0). Simulations showed that the mechanism of Ag collection affects the GC dynamics and the GC outputs concerning fast/slow (un)binding of B cells to FDC-presented Ags. In particular, clones with lower dissociation rates outcompete clones with higher association rates in Scenario-1, while remaining B cells from clones with higher association rates reach higher affinities. Accordingly, plasma cell and memory B cell populations were biased towards B-cell clones with lower dissociation rates. Without such probabilistic ruptures during the Ag extraction process (Scenario-2), the selective advantage for clones with very low dissociation rates diminished, and the affinity maturation level of all clones decreased to the reference level. Author summary Adaptive immunity is one of the vital defence mechanisms of the human body to fight virtually unlimited types of pathogens by producing antigen-specific high-affinity antibodies that bind to pathogens and neutralise them or mark them for further elimination. Affinity is a quantity used to measure and report the strength of interaction between antibodies and antigens that depends both on how fast antibodies bind to antigens (association rate) and how long the bond lasts (dissociation rate). The affinity of produced antibodies for a specific antigen increases in germinal centres through a process called affinity maturation, during which B cells with higher affinities have a competitive advantage and get positively selected to differentiate to antibody-producing plasma cells. Our research shows that the mechanism by which B cells capture Ag affects GC dynamics and GC output with respect to B-cell receptor kinetics. Notably, in a mechanism where rupture of CC-FDC bonds is possible during Ag extraction, B-cell clones with low dissociation rates outcompete clones with high association rates over time. Understanding how B cells get selected in germinal centres could help to develop an optimised and effective immune response against a disease through vaccination for a fast-operating and long-lasting immune response.