Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation

By Robert J. Johnston Jr., Amanda C. Poholek, D. Ditoro, I. Yusuf, D. Eto, Burton E. Barnett, A. Dent, J. Craft, Shane Crotty. Science, 2009

1,624 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. 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. We found 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 cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/09da415fb602533e521570afd5c44997c63f4e40

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Citations in the corpus

Bcl6 dependent T follicular helper cell differentiation diverges from effector cell differentiation during priming and depends on the gene Icos (2011, positive): “B cell-dependent Bcl6 induction for Tfh cell differentiation was further evidenced by rescuing Tfh cell differentiation in mMT mice by constitutive expression of Bcl6 in antigen-specific CD4+ T cells (Johnston et al., 2009).”
Follicular Helper T Cells. (2016, background): “Mechanistically, IL-2-dependent activation of STAT5 enhances BLIMP1 expression and displaces STAT3 from binding the BCL6 locus, thus inhibiting Tfh cell differentiation (50, 89, 135, 136).”
Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion (2011, background): “In contrast, B lymphocyte-induced maturation protein 1 (Blimp-1), a transcription repressor that regulates the function of Bcl-6, inhibits the generation of Tfh cells (Johnston et al., 2009).”
microRNA regulation of inflammatory responses. (2012, background): “This process of activation involves antibody secretion, class switch recombination, and somatic hypermutation [the latter two are mediated by the activationinduced cytidine deaminase (AID) enzyme], all of which involve interactions with CD4+ T cells (particularly the recently described Tfh cells) an”
Human Circulating PD-1+CXCR3−CXCR5+ Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses (2013, positive): “Given that Tfh cells can be a limiting factor for B cell responses (Johnston et al., 2009; Victora et al., 2010) and that Tfh cells are associated with better antibody responses to simian immunodeficiency virus (Petrovas et al.”
T follicular helper cell biology: A decade of discovery and diseases (2019, background): “, 2009), including the demonstration that the TFs Blimp1 and Bcl6 are potent reciprocal antagonists (Johnston et al., 2009) (Figure 1).”
Differentiation of Effector CD4 T Cell Populations (2010, positive): “STAT5 activation also regulates the activity of the Bcl6 promoter in B cells (97); in view of the expression of Bcl-6 in Tfh cells, this regulation raises the possibility that such an effect may be important in Tfh cell differentiation.”
T follicular helper cell differentiation, function, and roles in disease (2014, background): “Bcl6 also represses Blimp-1 (Johnston et al., 2009), which is strongly associated with non-Tfh cell fates (Figure 4).”