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Bcl6 expression specifies the T follicular helper cell program in vivo

ABSTRACT: T follicular helper (Tfh) cells play a pivotal role in germinal center reactions, which requires Bcl6 transcription factor. To analyze their relationships with other effector T cell lineages and their stability in vivo, we developed and analyzed a new Bcl6 reporter mouse alone or together with other lineage reporter systems. Assisted with genome-wide transcriptome analysis, we show substantial plasticity of T cell differentiation in the early phase of immune response. At this stage, CXCR5 appears to be expressed in a Bcl6-independent manner. Once Bcl6 is highly expressed, Tfh cells can persist in vivo and some of them develop into memory cells. Together, our results indicate Bcl6 as a bona fide marker for Tfh polarized program.

ORGANISM(S): Mus musculus

PROVIDER: GSE40068 | GEO | 2012/09/17

SECONDARY ACCESSION(S): PRJNA172725

REPOSITORIES: GEO

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Bcl6 expression specifies the T follicular helper cell program in vivo

Project description:T follicular helper (Tfh) cells play a pivotal role in germinal center reactions, which requires Bcl6 transcription factor. To analyze their relationships with other effector T cell lineages and their stability in vivo, we developed and analyzed a new Bcl6 reporter mouse alone or together with other lineage reporter systems. Assisted with genome-wide transcriptome analysis, we show substantial plasticity of T cell differentiation in the early phase of immune response. At this stage, CXCR5 appears to be expressed in a Bcl6-independent manner. Once Bcl6 is highly expressed, Tfh cells can persist in vivo and some of them develop into memory cells. Together, our results indicate Bcl6 as a bona fide marker for Tfh polarized program. Three group of samples, with 2 biological replicates within each group and total of 6 samples were analyzed.

2012-09-17 | E-GEOD-40068 | biostudies-arrayexpress

Type I Interferon induces binding of STAT1 to Bcl6: Divergent Roles of STAT-family transcription factors in the T follicular helper cell genetic program

Project description:CD4+ T follicular helper cells (TFH) are critical for the formation and function of B cell responses to infection or immunization, but also play an important role in autoimmunity. The factors that contribute to the differentiation of this helper cell subset are incompletely understood, although several cytokines including IL-6, IL-21 and IL-12 can promote TFH cell formation. Yet, none of these factors, nor their downstream cognate STATs, have emerged as non-redundant, essential drivers of TFH cells. This suggests a model in which multiple factors can contribute to the phenotypic characteristics of TFH cells. As type I interferons (IFNs) are often generated in immune responses, we set out to investigate if these factors are relevant to TFH cell differentiation. Type I IFNs promote Th1 responses, thus one possibility was these factors antagonized TFH-expressed genes. However, we show that type I IFNs (IFN-α/β) induced Bcl6 expression, the master regulator transcription factor for TFH cells, and CXCR5 and PD-1 (encoded by Pdcd1), key surface molecules expressed by TFH cells. In contrast, type I IFNs failed to induce IL-21, the signature cytokine for TFH cells. The induction of Bcl6 was regulated directly by STAT1, which bound to the Bcl6, Cxcr5 and Pdcd1 loci. These data suggest that type I IFNs (IFN-α/β) and STAT1 can contribute to some features of TFH cells but are inadequate in inducing complete programming of this subset. The role of STAT1 in type I interferon treated CD4+ T cells was investigated by Chip-seq of STAT1.

2014-01-22 | E-GEOD-51531 | biostudies-arrayexpress

Expression data from BCL6-YFP-positive Tfh cells, BCL6-YFP-negative Tfh cells, non-Tfh cells, and naïve helper T cells.

Project description:We found that a number of Tfh cells downmodulated BCL6 protein after their development, and we sought to compare the gene expression between BCL6-hi Tfh cells and BCL6-low Tfh cells. CD4+ T cells were sorted from immunized and non-immunized mice for RNA extraction and hybridization on Affymetrix microarrays. Bcl6yfp/+ OT-II cells were transferred to congenic recipient mice, and immunized with NP-OVA in CFA subcutaneously. Seven or ten days after immunization, cells were collected from draining lymph nodes, and sorted on FACSAria by the expression of CXCR5, PD-1 and BCL6-YFP. Naive CD4+ T cells were CD4+ CD44lo CD62Lhi cells from unimmunized mice.

2011-06-02 | E-GEOD-24574 | biostudies-arrayexpress

Transcription factor Achaete-Scute homologue 2 initiates T follicular helper cell development [ChIP-Seq]

Project description:In immune responses, activated T cells migrate to B cell follicles and develop to T follicular helper (Tfh) cells, a new subset of CD4+ T cells specialized in providing help to B lymphocytes in the induction of germinal centers 1-3. Although Bcl6 has been shown to be essential in Tfh cell function, it may not regulate the initial migration of T cells 4 or the induction of Tfh program as exampled by CXCR5 upregulation 5. Here, we show that the Achaete-Scute homologue 2 (Ascl2) gene that encodes a basic helix-loop-helix (bHLH) transcription factor 6, is selectively upregulated in its expression in Tfh cells. Ectopic expression of Ascl2 uniquely upregulates CXCR5 but not Bcl6 and downregulates CCR7 expression in T cells in vitro and accelerates T cell migration to the follicles and Tfh cell development in vivo. Combined transcriptome profiling and genome-wide occupancy analysis indicate that Ascl2 directly regulates Tfh-related genes while inhibits expression of Th1 and Th17 genes. Acute deletion of Ascl2 as well as blockade of its function with the Id3 protein in peripheral CD4+ T cells results in a failure in Tfh cell development and the germinal center response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh cell generation. Thus, Ascl2 critically and directly initiates Tfh cell development. Decide Ascl2 binding sites in CD4+ T cells

2014-01-01 | E-GEOD-52839 | biostudies-arrayexpress

Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro and in vivo follicular T helper cells

Project description:Follicular T helper cells (Tfh) provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated Protein (SAP) prevent GC formation due to defective T-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally-competent “Tfh-like” cells that expressed Interleukin-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2 and Th17 cells could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cell populations, supporting the concept of plasticity between Tfh and other Th cells. Epigenetic modifications were evaluated in ChIP-Seq studies by profiling histone H3K4 and H3K27 trimethylation marks between Th1, Th2, Th17, Tfh-like, and CXCR5+PD-1+ sorted Tfh-like in vitro generated T helper cell populations and ex vivo derived Tfh cells.

2012-01-05 | E-GEOD-32864 | biostudies-arrayexpress

Transcription factor Achaete-Scute homologue 2 initiates T follicular helper cell development [array]

2014-01-01 | E-GEOD-52838 | biostudies-arrayexpress

Type I Interferon induces binding of STAT1 to Bcl6: Divergent Roles of STAT-family transcription factors in the T follicular helper cell genetic program

2014-01-22 | GSE51531 | GEO

CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles

Project description:In response to infection, antigen-specific CD8+ T cells are primed in the T cell zone of secondary lymphoid organs and differentiate into cytotoxic effector T (TC) cells. Concurrently, CD4+ T cells differentiate into follicular helper T (TFH) cells that localize to B cell follicles and promote protective antibody responses. During unresolved infections, however, some viruses including human immunodeficiency virus (HIV) or Epsteinâ??Barr virus (EBV) escape immune control and persist in TFH cells and B cells, respectively. Exclusion of Tc cells from B cell follicles is thought to be a major mechanism of immune evasion. New strategies are therefore needed to eradicate infected cells in follicles for a permanent cure. Using mouse infection models and human samples, we here identify a specialized group of TC cells expressing the chemokine receptor CXCR5 that can selectively enter B cell follicles and eradicate infected TFH and B cells. We demonstrate that differentiation of these cells, which we term follicular cytotoxic T (TFC) cells, requires the transcription factors Bcl6, E2A and Tcf1, whereas the transcriptional regulators Blimp1, Id3 and Id2 inhibit their development. We demonstrate that Blimp1 and E2A directly regulate Cxcr5 expression, and together with Bcl6 and Tcf1 form a transcriptional circuit that guides the TFC differentiation. The identification of a follicular subset of TC cells has far reaching implications for developing better strategies for the control of infections that target B cells and TFH cells and for the eradication of B cell derived malignancies. There is no associated input. The E2A Bio-ChIP-seq was performed with total thymocytes from Tcf3Bio/Bio Rosa26BirA/BirA mice

2016-08-01 | E-GEOD-84974 | biostudies-arrayexpress

Continued Bcl6 expression prevents the transdifferentiation of established Tfh cells into Th1 cells during acute viral infection

Project description:By using a temporally-controlled system for the ablation of Bcl6 and Cxcr5 speficially in CD4 T cells, the requirements of both factors for the maintenance of Tfh cells were investigated

2020-10-06 | GSE142229 | GEO

Genome-wide analysis identifies Bcl6 repression of the IL-7R/STAT5 axis during T follicular helper (Tfh) cell differentiation

Project description:T follicular helper (Tfh) cell is a unique T cell subset specialized in promoting germinal center reactions. Bcl6 has been identified as an obligatory transcription factor in Tfh cells; however, the molecular mechanism underlying Bcl6 function still remains unknown. Here, we combined genome-wide Bcl6 occupancy and transcriptome profiling to systemically analyze Bcl6 targets in Tfh cells. We found that Bcl6 exhibits unique binding preferences in Tfh cells from those in Th9, B cells and macrophage and its binding is closely associated with decrease in 5-hydroxymethylcytosine (5hmC). Importantly, Bcl6 directly binds to the IL-7R/CD127 gene and suppresses its expression. Bcl6 also binds the same sequences recognized by signal transducer and activator of transcription (STAT) 5, downstream of IL-7R. Bcl6 promotes CD127loPDhi Tfh cell differentiation; deletion of the Bcl6 gene in T cells results in enhanced IL-7R-STAT5 signaling and substantial expansion of CD127hiPDlo non-Tfh cells. Our study thus systemically examines Bcl6-controlled regulatory networks and provides novel insights into its biological functions in Tfh cells.

2016-01-31 | GSE72188 | GEO

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