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; Monika Srivastava; Michelle Linterman; Lei Zheng; Nicholas Simpson; Julia I. Ellyard; Ian A. Parish; Cindy S. Ma; Qi Jing Li; Christopher R. Parish; Charles R. Mackay; Carola G. Vinuesa

doi:10.1016/j.immuni.2009.07.002

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, Monika Srivastava, Michelle Linterman, Lei Zheng, Nicholas Simpson, Julia I. Ellyard, Ian A. Parish, Cindy S. Ma, Qi Jing Li, Christopher R. Parish, Charles R. Mackay^*, Carola G. Vinuesa

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

965 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 RORγt and repressed IFN-γ 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 language	English
Pages (from-to)	457-468
Number of pages	12
Journal	Immunity
Volume	31
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2009.07.002
Publication status	Published - 18 Sept 2009

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Yu, D., Rao, S., Tsai, L. M., Lee, S. K., He, Y., Sutcliffe, E. L., Srivastava, M., Linterman, M., Zheng, L., Simpson, N., Ellyard, J. I., Parish, I. A., Ma, C. S., Li, Q. J., Parish, C. R., Mackay, C. R., & Vinuesa, C. G. (2009). The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment. Immunity, 31(3), 457-468. https://doi.org/10.1016/j.immuni.2009.07.002

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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 RORγt and repressed IFN-γ 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.",

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AU - Rao, Sudha

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AU - He, Yiqing

AU - Sutcliffe, Elissa L.

AU - Srivastava, Monika

AU - Linterman, Michelle

AU - Zheng, Lei

AU - Simpson, Nicholas

AU - Ellyard, Julia I.

AU - Parish, Ian A.

AU - Ma, Cindy S.

AU - Li, Qi Jing

AU - Parish, Christopher R.

AU - Mackay, Charles R.

AU - Vinuesa, Carola G.

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N2 - 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 RORγt and repressed IFN-γ 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.

AB - 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 RORγt and repressed IFN-γ 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.

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The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment

Abstract

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