Germinal Center B Cell Dynamics

Abstract

Germinal centers (GCs) are the site of antibody diversification and affinity maturation and as such are vitally important for humoral immunity. The study of GC biology has undergone a renaissance in the past 10 years, with a succession of findings that have transformed our understanding of the cellular dynamics of affinity maturation. In this review, we discuss recent developments in the field, with special emphasis on how GC cellular and clonal dynamics shape antibody affinity and diversity during the immune response.

Figure 1. Overview of the GC reaction

The GC is divided into two anatomical compartments, LZ and DZ, which are the sites of antigen-driven selection, and B cell proliferation and hypermutation, respectively. Affinity maturation happens in cycles of proliferation and SHM in the DZ followed by antigen-driven selection in the LZ. See text for further details. TBM, tingible body macrophage.

Figure 2. Dynamic control of B cell proliferation

The intensity of T cell help received in the LZ determines the number of division cycles a B cell will undergo in the DZ. On average, there are 2 S-phase initiation events in the LZ for each one in the DZ, indicating a ratio of 2 cell cycles per LZ-DZ cycle [(Gitlin et al., 2015), center panel]. A B cell that receives the minimum amount of help necessary for survival (left panel) would undergo only one cell cycle per LZ/DZ cycle, whereas a B cell that receives a strong Tfh cell-signal [either due to DEC-205 targeting or prior to a “clonal burst” (Tas et al., 2016); right panel] can undergo multiple cell cycles in the DZ without returning to the LZ.

Figure 3. Clonal dynamics in GCs

(A) Evolution of clonal diversity in GCs. Each color corresponds to a different clone (a distinct V(D)J rearrangement). Many potentially responsive cells are present in the pre-immune repertoire. Priming involves a competitive bottleneck, which prevents many lower-affinity B cells from entering the GC reaction. Despite this bottleneck, early GCs can still contain tens to hundreds of distinct clones, depending on the antigen used for immunization. Clonal diversity is lost at different rates of in different GCs, so that, by the end of the response to a protein antigen in alum, GCs are distributed across a wide range of clonal diversity. It is not yet known if all GCs would eventually become monoclonal were the response to last indefinitely. (B) Speculative model for the influence of stochastic “noise” (i.e., any factor not directly related to BCR affinity) on GC selection. B cells that fail to gain affinity upon SHM can still be rescued by stochastic factors (e.g., fortuitous encounters with antigen-rich FDC patches or with high-avidity Tfh cells). If the same positive stochastic factors act on a B cell whose affinity increased by SHM, a clonal burst may ensue.