From affinity selection to kinetic selection in Germinal Centre modelling

PLoS Comput Biol. 2022 Jun 3;18(6):e1010168. doi: 10.1371/journal.pcbi.1010168. eCollection 2022 Jun.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Affinity
  • Antigens
  • B-Lymphocytes*
  • Germinal Center*
  • Lymphocyte Activation
  • Receptors, Antigen, B-Cell

Substances

  • Antigens
  • Receptors, Antigen, B-Cell

Grants and funding

This work is supported by the Human Frontier Science Program 570 (RGP0033/2015) awarded to MMH, and COSMIC (www.cosmic-h2020.eu), which has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 765158 awarded to AHCvK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.