Fig. 4. Models of GC B cell differentiation.

a | Asymmetric fate model. Germinal centre (GC) B cells that interact with follicular helper T (T_FH) cells will undergo cellular polarization, resulting in unequal distribution of fate-altering molecules by daughter cells. Daughter cells inheriting fate-altering molecules that promote the expression of interferon regulatory factor 4 (IRF4) and MYC preferentially differentiate into plasma cells, whereas cells inheriting B cell lymphoma 6 (BCL-6), PAX5 and IL-21R either maintain GC B cell identity or differentiate into memory B cells (MBCs). b | Instructive fate model. The strength of T cell help and B cell receptor (BCR) signalling received by GC B cells dictates cell fate. Strong T cell help favours plasma cell differentiation and the dark zone state, whereas weak T cell help predisposes GC B cells to differentiate into MBCs or to undergo apoptosis. c | Decreasing-potential fate model. GC B cell fate is determined by the cumulative strength of T cell help and BCR signalling, accrued over the length of duration in the GC (days to weeks). As GC B cells undergo repeated rounds of cyclic re-entry, they progressively lose their ability to differentiate into MBCs, resulting in a shift towards increased plasma cell differentiation at late GC time points. d | Integrative fate model. GC B cells integrate both the current quality and the cumulative amounts of received signals when making cell fate decisions. GC B cells that have received less cumulative T cell help and BCR signalling need a stronger signal to differentiate into plasma cells. Conversely, GC B cells that have been in the GC longer and received more cumulative signals require a weaker signal to induce plasma cell differentiation. CD40L, CD40 ligand; MHC, major histocompatibility complex; TCR, T cell receptor.