Clonal and cellular dynamics in germinal centers

Abstract

Germinal centers (GCs) are the site of antibody affinity maturation, a process that involves complex clonal and cellular dynamics. Selection of B cells bearing higher-affinity immunoglobulins proceeds via a stereotyped pattern whereby B cells migrate cyclically between the GC's two anatomical compartments. This process occurs in a timeframe that is well suited to analysis by intravital microscopy, and much has been learned in recent years by use of these techniques. On a longer time scale, the diversity of B cell clones and variants within individual GCs is also thought to change as affinity maturation progresses; however, our understanding of clonal dynamics in individual GCs is limited. We discuss recent progress in the elucidation of clonal and cellular dynamics patterns.

Figure 1

Potential model for clonal dynamics during germinal center formation. GCs are seeded by a small fraction of the large repertoire of naïve B cells potentially responsive to the immunizing antigen by pre-GC competition for T cell help (Bottleneck #1), generating GCs composed of a limited number of clones. These GCs are then further purged from less competitive clones by a second round of competition for T cell help in the mature GC (Bottleneck #2), yielding the 1-3 clones observed in experiment.

Figure 2

Interplay of dynamics and selection in the germinal center reaction. B cells activated by antigen migrate to the T zone–follicle (TB) border, where they compete for a limiting number of helper T cells. Selected B cells migrate to the center of the follicle, where they proliferate extensively, giving origin to mature GCs. In these structures, GC B cells cycle between periods of proliferation and AID-driven mutation in the dark zone (DZ) and antigen-driven selection in the light zone (LZ). LZ-DZ cycling, selection for cyclic re-entry, and exit from the GC as memory (B_MEM) or plasma cells (PC) are likely to be controlled by interaction with a limiting number of T follicular helper (Tfh) cells. Changes in expression of selected G-protein coupled receptors required for the various steps in B cell migration are indicated in red. Cell phenotypes and cell-cycle stages are indicated in blue.

Figure 3

Tfh dynamics in germinal centers. From the B cell perspective, GCs are thought to be “islands” dominated by one or a few clones that differ between neighboring GCs. In contrast, Tfh cells freely exchange between GCs, and Tfh clones are distributed in approximately equal proportions among GCs from the same LN. Additionally, newly activated T cells (light green) can join and contribute to ongoing GC reactions.