Bcl6 Mediates the Development of T Follicular Helper Cells

By R. Nurieva, Yeonseok Chung, G. Martinez, Xuexian O. Yang, Shinya Tanaka, Tatyana D Matskevitch, Yi-hong Wang, C. Dong. Science, 2009

1,518 citations recorded by the source corpus.

T Follicular Helper Cell Differentiation When B cells respond to an infection, they often require help from CD4+ T cells to mount a proper response. It is thought that a subset of CD4+ effector T cells, called T follicular helper cells (TFH), performs this function. Several subsets of effector CD4+ T cells arise, depending on the type of infection, which have distinct transcriptional programs driving their differentiation. Whether this is also the case for TFH cells has not been clear (see the Perspective by Awasthi and Kuchroo). Nurieva et al. (p. 1001, published online 23 July) and Johnston et al. (p. 1006; published online 16 July) now demonstrate that the transcription factor Bcl6 is both necessary and sufficient for TFH differentiation and subsequent B cell–mediated immunity, suggesting that it is a master regulator of this lineage. Johnston et al. also show that expression of Bcl6 and the transcription factor, Blimp-1, are reciprocally regulated in TFH cells and that, when ectopically expressed, Blimp-1 inhibits TFH development. The transcription factors that regulate follicular T helper cell differentiation are identified. 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 cell subsets. Our data thus illustrate that Bcl6 is required for programming of TFH cell generation.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/6b4189b32c6b001f650893f28532ee8dcf747632

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In Immunology

Citations in the corpus

IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses (2010, background): “, 2002) and that IL-21 induces Bcl-6 expression in CD4+ T cells (Nurieva et al., 2009).”
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Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion (2011, background): “, 2006), which is necessary and sufficient for the development of Tfh cells in vivo (Johnston et al., 2009; Nurieva et al., 2009; Yu et al., 2009).”
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Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response (2011, background): “Coordinated Bcl-6 and Blimp-1 expression in T FR cells Bcl-6, the transcriptional regulator of the T FH subset, regulates key molecules required for follicular localization and functio”
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The regulation of IL-10 production by immune cells (2010, background): “In recent reports, BCL-6 was required for T follicular helper cell differentiation, but it inhibited the differentiation of other T H cell subsets, by direct interaction with T-bet, GATA3 and retinoic acid receptor-related orphan receptor-γt (RORγt”
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Bcl6 dependent T follicular helper cell differentiation diverges from effector cell differentiation during priming and depends on the gene Icos (2011, positive): “IL-21 and IL-6 are critical for different aspects B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.”