Bcl6 Mediates the Development of T Follicular Helper Cells

Abstract

A fundamental function of CD4 + helper T (T H ) cells is the regulation of B cell-mediated humoral immunity. Development of T follicular helper (T FH ) cells that provide help to B cells is mediated by the cytokines interleukin-6 and interleukin-21 but is independent of T H 1, T H 2, and T H 17 effector cell lineages. Here, we characterize the function of Bcl6, a transcription factor selectively expressed in T FH cells. Bcl6 expression is regulated by interleukin-6 and interleukin-21. Bcl6 overexpression induced T FH -related gene expression and inhibited other T H lineage cell differentiation in a DNA binding-dependent manner. Moreover, Bcl6 deficiency in T cells resulted in impaired T FH cell development and germinal center reactions, and altered production of other effector T cell subsets. Our data thus illustrate that Bcl6 is required for programming of T FH cell generation.

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

“…Thus, Bcl6 appears to use yet another mechanism to ensure the repressed state of PRDM1 in B cells in addition to the previously described competition for DNA binding with STAT3 [51], inhibition of AP-1 function [26] and direct binding to BRE1 in the PRDM1 gene [23]. Importantly, the mechanism that involves Bach2 would employ activation of transcription by Bcl6 as suggested for regulation of Cxcr5, Il6r and Il21r in the context of follicular T helper-cell development [11]. These findings warrant further investigation in vivo.…”

“…Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16].…”

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…Interestingly, Tfh cell differentiation relies on a set of transcription factors including Bcl6, BLIMP1, and IRF4 that also control late stages of B‐cell development. Bcl6 is essential for the induction of Tfh cell differentiation as the reciprocal repression of Bcl6 and BLIMP1 controls the development of Tfh vs. non‐Tfh CD4 + T helper cell populations (Johnston et al , 2009; Nurieva et al , 2009; Yu et al , 2009). At later stages, Bcl6 is required for stable Tfh effector commitment and the maintenance of memory Tfh cells (Liu et al , 2012; Ise et al , 2014).…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Factors that influence CD4 + cell Tfh‐lineage differentiation include the cytokine environment, ICOS ligation, and signaling via the T‐cell receptor (TCR). In mice, IL‐6 plays an important role in promoting Tfh cell generation and induces upregulation of the transcription factor B‐cell lymphoma 6 (Bcl6), which is a central regulator of Tfh differentiation 114, 115, 116. However, although there is evidence that IL‐6 can also promote Tfh differentiation in humans,117 it is a not a good inducer of Bcl6 expression in human CD4 + T cells 118, 119.…”

“…SAP expression is essential for GC formation,135 preventing inhibitory signaling through SLAM family member 6 (SLAMF6) to enable Tfh‐B cell adhesion,136 which is crucial for Tfh cell retention in GCs and provision of help to B cells. Bcl6 plays a central role in Tfh cell differentiation,115, 137, 138 but other transcription factors that act upstream and downstream of Bcl6 are also required (reviewed in 139). These include lymphoid enhancer‐binding factor 1 (LEF‐1) and T‐cell‐specific transcription factor 1 (TCF‐1), which act upstream of Bcl6 to promote Tfh cell differentiation140, 141, 142; basic leucine zipper transcription factor ATF‐like (Batf), which positively regulates Bcl6 and is important for IL‐4 expression143; interferon regulatory factor 4 (IRF4), which drives differentiation of IL‐12‐stimulated CD4 T cells to Tfh rather than Th1 cells144; achaete‐scute homolog 2 (Ascl2), which induces CXCR5 expression145; c‐Maf, which enhances expression of CXCR5, IL‐21, and IL‐4146; signal transducer and activator of transcription (STAT)s, STAT3 and 4 being particularly important for human Tfh cell differentiation and regulation of IL‐21 expression by human CD4 + T cells121, 147; and forkhead box protein O1 (FOXO1), which can both promote and inhibit Tfh cell differentiation 148.…”