The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment

Di Yu, Sudha Rao, Louis M Tsai, Sau K Lee, Yiqing He, Elissa L Sutcliffe, Mnika Srivastava, Michelle Linterman, Lei Zheng, Nicholas Simpson, Julia I Ellyard, Ian A Parish, Cindy S Ma, Qi-Jing Li, Christopher R Parish, Charles Reay Mackay, Carola G Vinuesa

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782 Citations (Scopus)

Abstract

Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.
Original languageEnglish
Pages (from-to)457 - 468
Number of pages12
JournalImmunity
Volume31
Issue number3
DOIs
Publication statusPublished - 2009

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