The Transcriptional Regulation of Germinal Center Formation

Abstract

Germinal centers (GCs) are essential structures of the humoral immune response, which form in the periphery in response to T cell dependent antigens. During the GC reaction, B cells undergo critical differentiation steps, which ultimately lead to the generation of antibodies with altered effector function and higher affinity for the selected antigen. Remarkably, many of the B cell tumors have their origin in the GCs; thus, understanding how the formation of these structures is regulated or deregulated is of high medical importance. This review gives an overview of the transcription factors that have been linked to the generation of GCs, and of their roles in the process.

Keywords: B cell development; germinal center (GCs); germinal center development; germinal center maintenance; hematopoiesis; plasma cell and memory B cell differentiation; transcription factors; transcriptional regulation.

Figure 1

Transcription factors controling GC formation. (A) Initiation of the GC reaction in follicular B cells. For clarity, TFs are indicated in black, while other molecules (e.g., receptors, cytokines, etc…) are in gray. B cell lymphoma 6 (BCL6) is essential for the initiation of germinal center, MEF2B, IRF8, IRF4, BLIMP1, and TP53 are involved in regulating the expression of Bcl6. BCL6 and Bach2 cooperatively (12) repress gene expression and thus allow the establishment of the germinal center B cell program. MEF2C is required for B cell survival post-antigen stimulation by upregulating the Bcl2l1. (B) Schematic representation of the dark zone and light zone of the GC. The different TFs involved are indicated, as well as some of the processes regulated (SHM, Proliferation, anti-apoptosis, CSR), see text for further details. In the GC DZ, AID is a key enzyme for SHM; its expression is controlled by PAX5, E2A, and IRF8. POLH, LIG4, and DNaseI are required for SHM and are highly expressed in DZ B cells. FOXO1 is a key factor for maintaining the GC DZ B cell program, CCND3 is preferentially expressed in GC DZ B cells and YY1 is required for GC DZ B cell proliferation and survival. NF-κB signaling and c-Myc are not essential for GC DZ B cells. In the GC LZ, CD40 signaling stimulated NF-κB further stimulates IRF4 expression, which suppresses Bcl6 gene (13, 14). PAX5, E2A, and IRF4 are key factors in regulating AID level. BATF, a downstream target of FOXO1, regulates germline transcripts (GLTs) in centrocytes. GLT levels are highly correlated with accessibility of AID in CSR.

Figure 2

Exit from the GC: memory vs. plasma cells. The top scheme highlights the cycling of B cells between the dark zone and the light zone. The gradients of the chemokine receptors CXCR4 and 5 are indicated, as well as the processes involved. GC B cells proliferate and undergo somatic hypermutation (SHM) in the GC DZ, and then migrate to the light zone where the affinity of mutated BCRs is selected. B cells with high affinity BCR are selected to reenter the DZ for several rounds of SHM or can differentiate into plasma cells. Memory B cells are mainly originated from B cells with low affinity BCR. The alternative fates of B cells exiting the GC are depicted at the bottom: plasma cells or memory B cells. The main networks that have been identified are indicated. In the plasma cell differentiation pathway, PU.1 and IRF8 negatively regulate plasma cell differentiation. IRF4 and BLIMP1 form the central axis in establishing plasma cells. BLIMP1 further suppresses the expression of Aicda, Bcl6, Pax5 and c-Myc genes and finally terminates the GC program. BLIMP1 positively regulates Xbp1 expression, makes the cells ready for antibody production and secretion. ABF1 promotes memory B cell differentiation and inhibits plasma cell differentiation. ZBTB32 and KLF2 are highly expressed in memory B cells.