Genome-wide Analysis Identifies Bcl6-Controlled Regulatory Networks during T Follicular Helper Cell Differentiation

•Bcl6 exhibits specific binding in mouse Tfh cells•Bcl6 binding correlates with decreased 5hmC•Bcl6 and STAT5 target the same binding sites•Bcl6 suppresses the IL-7R/STAT5 axis during Tfh cell generation

SummaryT follicular helper (Tfh) cell is a unique T cell subset specialized in promoting humoral immunity. B-cell lymphoma 6 protein (Bcl6) has been identified as an obligatory transcription factor in Tfh cells; however, the molecular mechanism underlying Bcl6 function remains largely unknown. Here, we defined Bcl6 target genes in Tfh cells by analyzing genome-wide Bcl6 occupancy together with transcriptome profiling. With consensus sequences being different from those in Th9, B cells, and macrophages, Bcl6 binding in Tfh cell was closely associated with a decrease in 5-hydroxymethylcytosine (5hmC). Importantly, Bcl6 promoted Tfh cell differentiation through antagonizing IL-7R (CD127)/signal transducer and activator of transcription (STAT) 5 axis; deletion of the Bcl6 gene in T cells resulted in enhanced IL-7R-STAT5 signaling and substantial expansion of CD127hi non-Tfh cells. Thus, our study systemically examines Bcl6-controlled regulatory networks and provides important insights into Bcl6’s biological functions in Tfh cells.

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