Affinity Selection in Germinal Centers: Cautionary Tales and New Opportunities

Abstract

Our current quantitative knowledge of the kinetics of antibody-mediated immunity is partly based on idealized experiments throughout the last decades. However, new experimental techniques often render contradictory quantitative outcomes that shake previously uncontroversial assumptions. This has been the case in the field of T-cell receptors, where recent techniques for measuring the 2-dimensional rate constants of T-cell receptor–ligand interactions exposed results contradictory to those obtained with techniques measuring 3-dimensional interactions. Recently, we have developed a mathematical framework to rationalize those discrepancies, focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of “catch bonds” and on the recent observations that B-cell synapses retract and pull antigen generating a “retracting force”, and propose some testable predictions that can lead to future research.

A Mechanical Assay for the Quantification of Anti-RBD IgG Levels in Finger-Prick Whole Blood

“…Such complexes likely exhibit a force-resistant characteristic known as catch-bond kinetics, characterized by increased lifetime when force increases within a force range of several pN. This possibility is suggested by the observation of catch-bond kinetics in antigen-specific TCR–pMHC complexes, where TCRs employ similar CDR loops to bind specific antigen epitopes. − Indeed, it has been proposed that mechanical force plays an important role in the B cell maturation process within the germinal center, potentially facilitating the specific selection of Ab-Ag bonds that can resist forces. Consequently, due to higher forces applied to nonspecific molecular complexes and likely catch-bond kinetics of specific IgG immunocomplexes, the force may selectively dissociate nonspecifically absorbed micobeads, resulting in a force-dependent increase in the signal-to-noise ratio, thus enhancing specificity.…”

From affinity selection to kinetic selection in Germinal Centre modelling

“…We could not find an experimental study for BcRs; however, in case the of TcR-pMHC binding, it has been shown that 2D on-rates are faster compared to 3D on-rates while 3D dissociation rates are higher than 2D [ 59 , 60 ]. Moreover, a unified mathematical framework has been proposed for addressing 2D/3D kinetic differences in the case of TcR-pMHC [ 61 ] that has been adopted to investigate BcR interaction with FDC-presented Ag concerning 2D/3D kinetic rates [ 62 ].…”

Antigen density and applied force control enrichment of nanobody-expressing yeast cells in microfluidics

“…12 Likewise, B cells physically pull on their target antigens to differentiate between a high affinity and a low affinity antigen, 1,13,14 though the existence of a catch-bond BCR or antibody has yet to be clearly established. 15 To our knowledge, only nanobodies (Nbs), corresponding to the variable fragment of the heavy-chain only antibodies (VHH) from the Camelidae serum 16 have been shown to have catch bond properties, as shown for a Nb binding to FcγRIII (CD16). 17 This result suggests that Nbs could be selected to deliver biophysical cues leading to optimal immune cell activation and function.…”