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 contradictory results 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.

Antigen binding kinetics are quite different for B-cell receptors and free antibodies

“…2D Isotype (×10 5 M −1 s −1 ) (×10 2 s −1 ) (×10 5 s −1 ) (×10 8 s −1 ) (×10 humoral immune response: B-cell receptors and antibodies. Here, we have extended previous works (7,8) to emphasize that, as it has already been acknowledged for TCRs (35,36), BCR-Ag binding kinetics cannot be inferred from their Ab-Ag counterparts. Specifically, the microscopic degrees of freedom (beyond pure spatial diffusion) and the mechanical properties of the Ab/BCR (flexibility) must be carefully and systematically analyzed to quantify) the impact on the effective rates, which, depending on the experimental setup, is the only observable information.…”

“…such that for 𝑘 + > 𝑘 + threshold , 𝑘 + eff approaches asymptotically a plateau given by 𝑘 + plateau = 𝑘 + 𝑑 𝑒 + 𝑘 − 𝑑 +𝑒 + , and 𝑘 − eff becomes proportional to the dissociation affinity constant (8).…”

“…The mean square angular deviation of a rotating molecule after a time t is given by (23, 29) where c is a constant particular for the geometry of the rotation, and D is the corresponding rotational diffusion constant. In particular, c = 2 for Fab twist and BCR Fc axial rotations, and c = 6 for Fab tilt and whole Ab rotations (8, 30). For such rotations, the mean rotational correlation time, denoted t 1rad , is the average time spent by the molecule to rotate 1 rad.…”

“…Calculations for and can be found in (8). The global rotational kinetic rates, e + and e − , can now be calculated applying the estimations for the rotational diffusion constants in Table 3 and for the angles ϕ 0 and δ (given at the end of section Mathematical derivation of the rotational rates ) to Eqns.…”

“…During a humoral immune response to protein Ags, B cells interact through their BCRs with their cognate Ag held in form of immunocomplexes on the membrane of specialized cell types, notably among them follicular dendritic cells (FDC) (4)(5)(6). This receptor-ligand interaction is similar to that of T-cell receptors (TCR) and their ligands, a complex of a protein-derived peptide with a molecule of the major histocompatibility complex (pMHC), in that it takes place in the context of a membrane-membrane interaction, and therefore in 2-dimensional (2D) conditions (7,8). Yet, the effective kinetic rate constants and affinity constants of BCR-Ag interactions have not been measured until now, except for a couple of Abs (9,10), due to a lack of adequate and easily implemented techniques.…”