Fig. 3. Transcriptional regulation of GC B cell differentiation.

Germinal centre (GC) B cell differentiation is regulated by the extent of signals received by the B cell through the antigen-engaged B cell receptor (BCR) and CD40 (via CD40L-expressing T cells). Boxes indicating signalling molecules are coloured yellow, transcription factors red, cytokines blue and downstream gene targets turquoise. A red cross indicates a pathway that is not functional under the condition illustrated. a | Weak BCR signalling and weak T cell help results in a failure of GC B cells to receive sufficient signals through the BCR and CD40 to induce KRAS and nuclear factor-κB (NF-κB)-driven repression of B cell lymphoma 6 (BCL-6) expression. Repression of BCL-2 expression by BCL-6 in these cells will result in apoptosis owing to a failure to receive sufficient survival signals. b | GC B cells that receive weak T cell help (transmitted via CD40) will not receive sufficient CD40-induced NF-κB signals to indirectly repress BTB domain and CNC homology 2 (BACH2). BACH2 promotes GC B cell survival through induction of the anti-apoptotic gene Bcl2l1 and repression of cyclin-dependent kinase inhibitor family genes (Cdkn1a, Cdkn2a). BACH2 also represses B lymphocyte-induced maturation protein 1 (BLIMP1) and, accordingly, restricts plasma cell differentiation. The continued survival of B cells that receive weak T cell help is dependent on receiving sufficient BCR-driven KRAS signalling to repress BCL-6 expression. Exposure to T cell-derived IL-4 and IL-21 normally stabilizes BCL-6 expression in GC B cells. However, B cells that receive weak T cell-derived CD40 will also have low exposure to IL-4 and IL-21, resulting in impaired BCL-6 expression and induction of BCL-6-repressed genes such as haematopoietically expressed homeobox (Hhex) and Bcl2. HHEX interacts with the co-repressor transducin-like enhancer 3 (TLE3) to further repress BCL-6 expression and promote memory B cell development through the upregulation of BCL-2 and the transcription factor Sloan-Kettering Institute (SKI). c | GC B cells that receive intermediate T cell help receive both phosphoinositide 3-kinase (PI3K)/AKT and NF-κB signalling, resulting in phosphorylation of the ribosomal protein S6 (pS6) and expression of MYC. pS6 and MYC subsequently induce expression of forkhead box O1 (FOXO1) and activating enhancer binding protein 4 (AP4), respectively, ultimately leading to the adoption of the highly proliferative dark zone state. Intermediate levels of CD40 signalling do not drive sufficient NF-κB signalling to repress expression of the ubiquitin ligase CBL, allowing CBL to continue to repress interferon regulatory factor 4 (IRF4) expression and prevent plasma cell differentiation. d | GC B cells that receive strong T cell help receive both PI3K/AKT and NF-κB signalling. Strong NF-κB signalling represses CBL expression and allows for upregulation of IRF4. IRF4 represses BCL-6 expression and leads to expression of BLIMP1 and plasma cell differentiation.