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

Abstract

HighlightsB cell help, afforded by T cells, is an essential process of adaptive immunity.The transcription factor B cell lymphoma 6 (Bcl6), by serving as an apex of a repressor-of-repressors network, can provide further insights into follicular helper T cell (T FH ) regulation in mice and humans.Bcl6 is essential for T FH differentiation and harbors various significant activities, including inhibition of Prdm1 expression.We posit that Bcl6 can control non-T FH and T FH genes by at least two modes of action: direct repression and repressionof-repressor mechanisms.

ZBTB Transcription Factors: Key Regulators of the Development, Differentiation and Effector Function of T Cells

“…CD28 signal quickly upregulates the H3K36 methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), which specifically modifies the gene body of Bcl6 and hence enhances its transcription (116). Thereafter, multiple TFs and signaling pathways are employed to enhance/maintain BCL6 levels (114). For instance, by binding to IL-6R whose expression is mediated by TCF7, IL-6 enhances the expression BCL6 in CD4 + T cells via STAT1/3, and thus promotes the differentiation of Tfh cells both in vitro and in vivo (117)(118)(119).…”

“…Apart from differentiation, BCL6 is also essential for the maintenance of Tfh cells in vivo, as temporal ablation of BCL6 by tamoxifen (CD4-Cre ERT2 ) induces the transdifferentiation of established Tfh cells into TBX21 + Th1 cells during acute viral infection (121). Intriguingly, although BCL6 antagonizes the differentiation of non-Tfh subsets (Th1, Th2 and Th17, etc) by directly repressing their lineage-defining TFs (Tbx21, Gata3 and Rorc, etc) as mentioned above (114), it is lowly expressed in these Th subsets and modulates their functions via multiple mechanisms (Figure 2A). In Th1 cells, BCL6 is guided by TBX21, via the TBX21-BCL6 complex which masks BCL6's DNA binding ZF domains, to promoter regions and represses the transcriptional activation of Socs1/3, Tcf7 and Ifng, whereas excess amounts of BCL6 induce Tfh gene expressions (122,123).…”

“…The well-studied BCL6 (B cell lymphoma-6, also known as ZBTB27) was initially identified as an oncogene frequently translocated/hypermutated in diffuse B cell lymphoma (DLBCL) and follicular lymphoma (FL) cells ( 22 ). In T-cell compartment, BCL6 not only regulates the differentiation of Th cells, but also impacts the generation & maintenance of Tm cells ( Figures 2A, B ) ( 114 , 115 ).…”

“…BCL6 is indispensable for germinal center (GC) reactions as it drives the differentiation of both GC B cells and Tfh cells ( 22 , 114 ). BCL6 is induced as early as the first division after T-cell activation in a CD28-dependent manner.…”

“…Subsequently, BCL6 directly binds and represses a set of TFs ( Prdm1 , Tbx21 , Gata3, Rora/Rorc and Runx2/3 , etc), signaling transducers ( Stat5 ), cytokines ( Il4 & Il17a ) and chemokine receptors ( Selplg, Ccr7 and Gpr183 , etc) that drives Th cells towards non-Tfh fates/functions. At the meantime, BCL6 indirectly upregulates many essential functional molecules, such as CXCR5, ICOS, PD1 and IL-6R, likely by repression-of-repressor mechanisms through targeting a panel of TFs including Prdm1 , Id2 , Runx2/3 and Klf2 ( 114 ). An extensive review on the regulation of BCL6 expression as well as BCL6-mediated transcriptional regulation in Tfh cells has just been published by Choi and Crotty elsewhere ( 114 ).…”