Linking signaling and selection in the germinal center

Abstract

Summary Germinal centers (GC) are sites of rapid B‐cell proliferation in response to certain types of immunization. They arise in about 1 week and can persist for several months. In GCs, B cells differentiate in a unique way and begin to undergo somatic mutation of the Ig V regions at a high rate. GC B cells (GCBC) thus undergo clonal diversification that can affect the affinity of the newly mutant B‐cell receptor (BCR) for its driving antigen. Through processes that are still poorly understood, GCBC with higher affinity are selectively expanded while those with mutations that inactivate the BCR are lost. In addition, at various times during the extended GC reaction, some GCBC undergo differentiation into either long‐lived memory B cells (MBC) or plasma cells. The cellular and molecular signals that govern these fate decisions are not well‐understood, but are an active area of research in multiple laboratories. In this review, we cover both the history of this field and focus on recent work that has helped to elucidate the signals and molecules, such as key transcription factors, that coordinate both positive selection as well as differentiation of GCBC.

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

“…Changes in BCR signal strength can, however, have implications for GC B cell fate(Ochiai et al, 2013;Phan et al, 2006;Turner and Ke, 2018). Current models of GC B cell differentiation indicate that high strength of signal received in the LZ promotes PC differentiation whereas low strength of signal fosters MBC differentiation or death(Ise and Kurosaki, 2019;Shlomchik et al, 2019). Our data are generally consistent with the notion that high antigen signal strength favors PC differentiation but also reveal several additional mechanistic insights into GC biology during chronic infection.…”

“…It remained unclear where chronic infection caused diversion in the stepwise, cyclic scheme of GC B cell differentiation. A typical progression through the GC involves rapid proliferation and somatic hypermutation in the DZ, exit from cell cycle and testing of BCR, and then key decision points in the LZ to initiate either DZ re-entry or begin a PC or MBC differentiation path (Mesin et al, 2016;Shlomchik et al, 2019;Stewart et al, 2018). To understand how chronic infection altered these biological decision points in the GC, we next applied pseudotime analysis to the single-cell data to infer differentiation trajectories and cluster relationships (Qiu et al, 2017b(Qiu et al, , 2017a.…”

“…Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC) (Cyster and Allen, 2019;Plotkin, 2008). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help (Mesin et al, 2016;Shlomchik et al, 2019). Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection.…”

BAFF inhibition in SLE—Is tolerance restored?

“…86 In addition, those B cells that acquire autoreactivity as a result of somatic mutation are censored before they reach the memory compartment. [87][88][89][90] Despite these data, evidence from both animal and human studies implicates dysregulated GCs as an important site for B cell tolerance breaks.…”

Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

“…Survival and progression in the GC are driven in a Darwinian fashion by competition for limiting T cell help. Many if not all possible fates for GC B cells (cell cycle, deletion, memory and plasma cell differentiation) require T cell input (31). This is in part because GC B cell signalling is intrinsically rewired to depend on T cell help (31).…”