Germinal Centre Shutdown

Abstract

Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, 'normal' GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question - what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.

Keywords: B cell lymphoma; antibody responses; chronic germinal centres; ectopic germinal centres; germinal centre shutdown; vaccination.

Figure 1

Schematic representation of the different fates of GC B cells that lead to GC volume changes: GC B cells proliferate in the DZ and increase in number. SHM accompanying proliferation might induce deleterious mutations in the BCR gene of some of the B cells, thus activating apoptosis in these GC B cells. Lack of acquisition of antigen, survival signals from FDCs and signals from Tfh cells lead to the apoptosis of GC B cells in the LZ. On the other hand, successful acquisition of these signals could result in the differentiation of the GC B cells into effector cell types such as memory and plasma cells that exit the GC. Alternatively, selected cells can move back to the DZ by a process termed recycling and undergo further rounds of divisions thus contributing to an increase in number of GC B cells. Green and red arrows represent processes that increase or decrease the GC volume, respectively and influence GC shutdown. GC, Germinal Centres; BCR, B cell receptor; FDC, Follicular Dendritic Cells, Tfh, T follicular helper cells, B, GC B cells; Tfr, T follicular regulatory cells; PC, Plasma cell; B_m , Memory B cell; Ag, Antigen.

Figure 2

Summary of alterations seen in GC cell types at late stages of GC reaction. These alterations might play a causal role in GC shutdown by influencing the fate decisions of GC B cells shown in Figure 1 or act as a contributing factor to GC shutdown. GC, Germinal centre; FDCs, Follicular dendritic cells; Tfr, T follicular regulatory cells; Tfh, T follicular helper cells, B, GC B cells; TCR, T cell receptor; BCR, B cell receptor; PC, Plasma cell; B_m , Memory B cell; Ag, Antigen.