Transcription factors regulating B cell fate in the germinal centre

Abstract

Diversification of the antibody repertoire is essential for the normal operation of the vertebrate adaptive immune system. Following antigen encounter, B cells are activated, proliferate rapidly and undergo two diversification events; somatic hypermutation (followed by selection), which enhances the affinity of the antibody for its cognate antigen, and class-switch recombination, which alters the effector functions of the antibody to adapt the response to the challenge faced. B cells must then differentiate into antibody-secreting plasma cells or long-lived memory B cells. These activities take place in specialized immunological environments called germinal centres, usually located in the secondary lymphoid organs. To complete the germinal centre activities successfully, a B cell adopts a transcriptional programme that allows it to migrate to specific sites within the germinal centre, proliferate, modify its DNA recombination and repair pathways, alter its apoptotic potential and finally undergo terminal differentiation. To co-ordinate these processes, B cells employ a number of 'master regulator' transcription factors which mediate wholesale transcriptomic changes. These master transcription factors are mutually antagonistic and form a complex regulatory network to maintain distinct gene expression programs. Within this network, multiple points of positive and negative feedback ensure the expression of the 'master regulators', augmented by a number of 'secondary' factors that reinforce these networks and sense the progress of the immune response. In this review we will discuss the different activities B cells must undertake to mount a successful T cell-dependent immune response and describe how a regulatory network of transcription factors controls these processes.

Keywords: B cell; cell differentiation; gene regulation; transcription factors; transcriptomics.

Figure 1

Germinal centre structure, formation and B cell movement. (a) The anatomical structure of the lymph node prior to commencement of an immune response. In addition, the location of the resident cell populations and movement of cells/immunogens are indicated. Naive T cells (light yellow) move into the T cell zone (paracortex) from the circulation, where resident dendritic cells (DCs) (light green) collect and display antigen (purple triangle). Circulating naive B cells move into B cell follicles, located within the interfollicular region (cortex), where they sample antigen displayed by follicular DCs (FDCs) (dark green). The location of subcapsular macrophages (purple) is also shown. (b) The cell interactions and movements associated with the early stages of the immune response. Initially (day 1 of the response) naive T cells are primed (dark orange cell) following recognition of their cognate antigens, presented by DCs in the T cell cortex (light pink). The T cells then move to the interfollicular regions (dark pink), where they mature into T follicular helper (Tfh) cells. Similarly, naive B cells are activated (dark blue cell) by their cognate antigen displayed on the surface of FDCs and move out of the follicle into the interfollicular region. By day 2 of the response, antigen‐primed B cells find their cognate Tfh cells to form stable interactions and become fully activated. (c) The early stages of germinal centre (GC) formation. Cognate B/T cells move back into the B cell follicle where B cells acquire a GC fate, undergoing rounds of rapid proliferation. This B cell clonal expansion starts to form the GC. By days 4–5 some activated B cells move into the subcapsular sinus (SCS – light green) and differentiate into short‐lived plasmablasts (d). The final architecture, cellular composition and cell movement within the mature GC is shown with the dark zone composed of rapidly proliferating centroblasts and light zone containing centrocytes undergoing affinity maturation by selection with Tfh and FDCs. Here, non‐selected cells undergo apoptosis, while some cells move out of the GC to differentiate into long‐lived plasma cells (PCs).

Figure 2

Regulators of germinal centre (GC) activities and B cell fate, showing the expression of the critical transcription factors that control B cell fate at different stages of B cell maturity, from naive B cells (light blue), through activated GC B cells (dark blue) to plasmablasts and plasma cells. At the transition between each stage (indicated by thick arrows) the critical change in transcription factor expression is shown (up‐/down‐regulation of factors is indicated by small arrows). The receptors responsible for B cell movement/localizsation are also shown.

Figure 3

Regulatory network controlling the germinal centre (GC) response. The regulatory network that coordinates the GC response is illustrated at the three main stages of B cell differentiation, from naive B cell through to activated GC B cell and finally mature plasma cell. The ‘master regulators’ expressed in each cell type are shown in blue boxes, while their critical target genes/pathways are given below. The ‘secondary factors’ that augment the master regulators are shown above. The regulatory interactions that exist between each of the transcription factors are depicted by either arrows (stimulatory) or flat‐headed arrows (inhibitory). Each transcription factor and its corresponding interactions is colour‐coded. The activation of XBP1 brought about by the relief of paired box protein 5 (PAX5) repression is represented by a dashed line.