Figure 1. Effectors driving the switch between EF or GC responses.

Effector molecules can influence the dominance of EF or GC responses by directly acting on B cells, or indirectly by promoting or repressing TFH differentiation. IL-6 drives TFH differentiation, thereby promoting GC, while pro-inflammatory molecules (IL-12, IFNγ, TNFα, and IL-2) repress TFH and downstream GC. IL-12 also promotes T cell proliferation, therefore a balance of proliferation and repression of TFH differentiation must be struck for optimal TFH/GC formation. Additional unknown signals can drive the development of T extrafollicular helper cells (T_EFH), which promote EF responses. BLyS and APRIL act directly on B cells through the receptor TACI to promote EF responses. TLR7 promotes GC while TLR9 inhibits GCs, although the mechanisms behind these divergent effects are unclear. EF and GCBC both undergo somatic hypermutation (SHM), hence the main difference between them is likely the efficiency of obtaining T cell help that induces further rounds of proliferation and mutation. EF and GC responses both generate MBC. However, subsets of MBC have different origins. CD80^- PD-L2^- (double negative, DN) MBC are primarily formed prior to GC, and CD80⁺ PD-L2⁺ (double positive, DP) are predominantly from GC. LLPC are the latest to form and arise almost entirely, if not exclusively, from GCs.