Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), 9420 Athena Circle, La Jolla, CA 92037, USA.; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92037, USA.
Effective B cell-mediated immunity and antibody responses often require help from CD4(+) T cells. It is thought that a distinct CD4(+) effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. Here, we show that expression of the transcription factor Bcl6 in CD4(+) T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central yet opposing roles in TFH differentiation.
PMID: 19608860 [PubMed - as supplied by publisher]
Science. 2009 Jul 23. [Epub ahead of print]
Bcl6 Mediates the Development of T Follicular Helper Cells.
Department of Immunology, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
A fundamental function of CD4(+) helper T (Th) cells is the regulation of B cell-mediated humoral immunity. Development of T follicular helper (Tfh) cells that provide help to B cells is mediated by the cytokines interleukin-6 and interleukin-21, but is independent of Th1, Th2, and Th17 effector cell lineages. Here, we characterize the function of Bcl6, a transcription factor selectively expressed in Tfh cells. Bcl6 expression is regulated by interleukin-6 and interleukin-21. Bcl6 overexpression induced Tfh-related gene expression and inhibited other Th lineage cell differentiation in a DNA binding-dependent manner. Moreover, Bcl6 deficiency in T cells resulted in impaired Tfh cell development, and germinal center reactions, and altered production of other effector T cells subsets. Our data thus illustrate that Bcl6 is required for programming of Tfh cell generation.
PMID: 19628815 [PubMed - as supplied by publisher]
The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment.
Immunology and inflammation, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Immunology and Genetics, John Curtin School of Medical Research, Canberra, ACT 2601, Australia.
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.
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