T follicular helper (Tfh) cells provide essential help to B cells in germinal center (GC) reactions. Bcl6 is the obligatory lineage transcription factor in Tfh cells. Here, we examined the molecular pathways that induce Bcl6 gene expression and underscore Bcl6-dependent function during Tfh cell commitment. Integration of genome-wide Bcl6 occupancy in Tfh cells and differential gene expression analyses suggested an important role for the transcription factor Tox2 in Tfh cell differentiation. Ectopic expression of Tox2 was sufficient to drive Bcl6 expression and Tfh development. In genome-wide ChIP-seq analyses, Tox2-bound loci associated with Tfh cell differentiation and function, including Bcl6. Tox2 binding was associated with increased chromatin accessibility at these sites, as measured by ATAC-seq. Tox2-/- mice exhibited defective Tfh differentiation, and inhibition of both Tox2 and the related transcription factor Tox abolished Tfh differentiation. Thus, a Tox2-Bcl6 axis establishes a transcriptional feed-forward loop that promotes the Tfh program.

中文翻译：

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转录因子Tox2通过调节染色质的可及性来驱动T卵泡辅助细胞的发育。

T滤泡辅助细胞（Tfh）为生发中心（GC）反应中的B细胞提供了必不可少的帮助。Bcl6是Tfh细胞中的强制性谱系转录因子。在这里，我们检查了在Tfh细胞定居过程中诱导Bcl6基因表达并强调Bcl6依赖性功能的分子途径。Tfh细胞中全基因组Bcl6占用的整合和差异基因表达分析表明，转录因子Tox2在Tfh细胞分化中具有重要作用。Tox2的异位表达足以驱动Bcl6表达和Tfh发育。在全基因组ChIP-seq分析中，与Tfh细胞分化和功能相关的Tox2结合位点，包括Bcl6。如ATAC-seq所测，Tox2结合与这些位点上染色质的可及性增加有关。Tox2-/-小鼠表现出缺陷的Tfh分化，并且对Tox2和相关转录因子Tox的抑制都废除了Tfh分化。因此，Tox2-Bcl6轴建立了促进Tfh程序的转录前馈环。