Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity

Abstract

Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs) arising from EF sites, followed by GC producing somatically mutated memory B cells (MBC) and long-lived plasma cells. However, somatic hypermutation (SHM) and affinity maturation can take place at both sites, and a substantial fraction of MBC are produced prior to GC formation. Infection responses range from GC responses that persist for months to persistent EF responses with dominant suppression of GCs. Here, we review the current understanding of the functional output of EF and GC responses and the molecular switches promoting them. We discuss the signals that regulate the magnitude and duration of these responses, and outline gaps in knowledge and important areas of inquiry. Understanding such molecular switches will be critical for vaccine development, interpretation of vaccine efficacy and the treatment for autoimmune diseases.

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.