Factors Determining Clonal Selection in Germinal Centres

Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation (SHM) in dark zones (DZs) and selection in light zones (LZs).

Current models state that, following SHM, DZ cells exit cell cycle and move to LZs to test their newly mutated B cell receptors by competing T cell help.

High affinity B cells preferentially “win” in receiving help, and this causes them to undergo cyclic reentry (defined by S phase initiation and DZ re-entry).

We recently demonstrated the possible existence of a second checkpoint, because BCR expression is required for LZ entry. We propose testing the nature of BCR-dependent signals required for this (e.g. cognate vs tonic signaling).

Next, we will re-examine the fundamental principle that affinity enhancements are favored by LZ cells competing for cyclic re-entry promoting cues. In unpublished studies, we unexpectedly find that T cell help in not required for initiating cyclic re-entry.

We will therefore test whether LZ cells compete for other non-T cell-derived cues, or whether instead cyclic re-entry is controlled independently of selection events.

Finally, we will investigate whether GCs utilize innate cell types and signaling pathways for sensing the continued presence of foreign material and for determining GC longevity.