The Transcription Factor Tox2 Drives T Follicular Helper Cell Development via Regulating Chromatin Accessibility

• Published in: Immunity (Cambridge, Mass.) Mass.), 2019-11, Vol.51 (5), p.826-839.e5
• Main Authors: Xu, Wei, Zhao, Xiaohong, Wang, Xiaoshuang, Feng, Han, Gou, Mengting, Jin, Wei, Wang, Xiaohu, Liu, Xindong, Dong, Chen
• Format: Article
• Language: English
• Subjects: Accessibility; Animals; Bcl-6 protein; Bcl6; Binding sites; Cell adhesion & migration; Cell differentiation; Cell Differentiation - genetics; Chromatin; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly; Cytokines; Differentiation (biology); Ectopic expression; Gene expression; Gene Expression Regulation; Gene Knockdown Techniques; Genetic engineering; Genomes; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Lymphocytes; Lymphocytes B; Mice; Mice, Knockout; Occupancy; Proto-Oncogene Proteins c-bcl-6 - metabolism; Statistical analysis; T cell receptors; T follicular helper cell; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Tox; Tox2; Transcription factors; Transcription Factors - metabolism; transcriptional regulation
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2019.10.006

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. [Display omitted] •Tox2 is highly expressed in Tfh cells and regulated by Bcl6 and STAT3•Forced expression of Tox2 drives Tfh development•Tox2 directly binds to Tfh-associated genes, promoting chromatin accessibility•Combined deletion of Tox2 and Tox abrogates Tfh development T follicular helper (Tfh) cells provide help to B cells in germinal center reactions and are essential to humoral immunity. Xu et al. define a feed-forward loop mediated by the transcription factors Bcl6 and Tox2 that promotes and establishes the Tfh program.