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Dr. Chen Dong’s group reveals a critical role for Tox2 and Tox in regulating Tfh differentiation

 

On November 12, 2019, Dr. Chen Dong’s group at the Tsinghua University Institute for Immunology published a research article entitled“The Transcription Factor Tox2 Drives T Follicular Helper Cell Development via Regulating Chromatin Accessibility”in Immunity. This work revealed that Bcl6 regulates the generation of Tfh cells, at least in part, via up-regulating Tox2 and Tox expression during Tfh differentiation. Mechanistically, Tox2 directly regulates a core set of Tfh-associated genes by activating their chromatin accessibility.

T follicular helper (Tfh) cells are a specialized effector CD4+ T cell subset required for germinal center (GC) formation. Although Bcl6 is the obligatory lineage transcription factor in Tfh cells, the molecular mechanisms underlying the essential function of Bcl6 in Tfh cell biology are only partially understood. 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.

Dr. Chen Dong is the corresponding author of this article. Ph.D. student Wei Xu is the first author. Ph.D. students Xiaohong Zhao, Xiaoshuang Wang, Han Feng and Mengting Gou also contributed to this study. The work was supported by National Natural Science Foundation of China, Beijing Municipal Science and Technology and Ministry of Science and Technology of China. C.D. is a FViL Investigator.

Links: https://www.cell.com/immunity/fulltext/S1074-7613(19)30450-9