Bcl6-Mediated Transcriptional Regulation of Follicular Helper T cells (TFH)

Abstract

Follicular helper T cells (T_FH) are essential B cell-help providers in the formation of germinal centers (GCs), affinity maturation of GC B cells, differentiation of high-affinity antibody-producing plasma cells, and production of memory B cells. The transcription factor (TF) B cell lymphoma 6 (Bcl6) is at the center of gene regulation in T_FH biology, including differentiation and function, but how Bcl6 does this, and what additional TFs contribute, remain complex questions. This review focuses on advances in our understanding of Bcl6-mediated gene regulation of T_FH functions, and the modulation of T_FH by other TFs. These advances may have important implications in deciphering how repressor TFs can regulate many immunological cell types. An improved understanding of T_FH biology will likely provide insights into biomedically relevant diseases.

Keywords: Bcl6; cell differentiation; follicular helper T cells; gene expression; germinal center; transcription factors.

Figure 1.. The differentiation process of T_FH and GC-T_FH cells in mice

T_FH differentiation is a multi-factorial, multi-stage process. Bcl6 is the lineage-defining TF for T_FH differentiation. T_FH differentiation is initiated by dendritic cell (DC) priming. CD4⁺ T cells migrate to the T-B border of secondary lymphoid organs where T_FH cells interact with cognate B cells. B cells provide additional signals to T_FH cells to drive GC-T_FH differentiation. This figure was created using BioRender (https://biorender.com/).

Figure 2.. Model of control of T_FH differentiation and function by Bcl6

(A) Bcl6 can control non-T_FH and T_FH genes by at least two mode-of-action: (i) direct repression and (ii) repression-of-repressor mechanisms. Bcl6 directly binds and represses a set of genes for alternative cell fates, cytokines, receptors, and migratory genes. Bcl6 indirectly upregulates important functional molecules by repression-of-repressor mechanisms via a set of Bcl6 target TFs (Bcl6-r TFs), including Prdm1, Id2, Runx2, Runx3, and Klf2. Illustration concept based on [43]. (B) Runx2 and Runx3 repress important T_FH molecules, including Cxcr5, Icos, and Cd200, downstream of Bcl6. (C) Klf2 represses important T_FH molecules, including Cd200, Pdcd1, Icos, Il6ra, Il21, and Il4, downstream of Bcl6 [26].

Figure 3.. The transcription factor network of T_FH cell differentiation in mice

The transcriptional regulatory network of T_FH cell differentiation is shown. Transcription factors activating (arrows) or repressing (closed lines) the genes associated with T_FH cell differentiation and function are described. The major Bcl6-target transcription factors (Bcl6-r TFs) are indicated in dark blue boxes. Illustration inspired by [9]. This figure was created using BioRender (https://biorender.com/).