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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states [ATAC-Seq]

ABSTRACT: Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies. However, the signals that promote Tfh development after initial differentiation are unknown. Here we use fate mapping and reporter strategies to show that, after initial differentiation, Tfh cells transition from a progenitor-like Tfh (Tfh-Prog) stage to an IL-21-expressing fully developed Tfh (Tfh-Full) stage which is regulated by follicular regulatory T (Tfr) cells. Using single cell RNA sequencing and epigenomic analysis, we uncover additional developmental stages including an early Tfh transitory (Tfh-Trans) stage prior to full development, as well as an Tfh-Ex stage that occurs after full development marked by loss of IL-21 expression. The transcriptional and epigenetic landscape is formed in the Tfh-Transitory stage and is maintained throughout the Tfh-Ex state, suggesting terminal development. We also find the transcription factor Foxp1 regulates the transitions between these stages in Tfh cells to balance the ratio of stem-like progenitor and effector Tfh cells. Through selective in vivo deletion of Tfh-Full and Tfh-Ex cells, we show that these cells control antigen-specific germinal center formation, maintenance and somatic hypermutation at distinct stages of responses to a SARS-CoV-2 vaccine. Together, these studies demonstrate the transitionary phases of Tfh development and how control of the progression through these stages regulates humoral immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE225722 | GEO | 2023/10/20

REPOSITORIES: GEO

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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states [scRNA-seq]

Project description:Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies. However, the signals that promote Tfh development after initial differentiation are unknown. Here we use fate mapping and reporter strategies to show that, after initial differentiation, Tfh cells transition from a progenitor-like Tfh (Tfh-Prog) stage to an IL-21-expressing fully developed Tfh (Tfh-Full) stage which is regulated by follicular regulatory T (Tfr) cells. Using single cell RNA sequencing and epigenomic analysis, we uncover additional developmental stages including an early Tfh transitory (Tfh-Trans) stage prior to full development, as well as an Tfh-Ex stage that occurs after full development marked by loss of IL-21 expression. The transcriptional and epigenetic landscape is formed in the Tfh-Transitory stage and is maintained throughout the Tfh-Ex state, suggesting terminal development. We also find the transcription factor Foxp1 regulates the transitions between these stages in Tfh cells to balance the ratio of stem-like progenitor and effector Tfh cells. Through selective in vivo deletion of Tfh-Full and Tfh-Ex cells, we show that these cells control antigen-specific germinal center formation, maintenance and somatic hypermutation at distinct stages of responses to a SARS-CoV-2 vaccine. Together, these studies demonstrate the transitionary phases of Tfh development and how control of the progression through these stages regulates humoral immunity.

2023-10-20 | GSE236876 | GEO

Foxp1 is a rate-limiting and essential negative regulator of Tfh cell differentiation

Project description:CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) and high-affinity antibody responses. Yet the regulation that determines the initial development of Tfh cells is still largely unknown. Here we find that transcription factor Foxp1, previously shown to be essential in maintaining T cell quiescence, is a rate-limiting and essential negative regulator of Tfh cell differentiation. NaM-CM-/ve CD4+ T cells constitutively express Foxp1A, and stimulation through the T cell receptor (TCR) transiently induces the expression of a shorter Foxp1D isoform. In T cell-dependent (TD) humoral responses, CD4+ T cells deficient in all Foxp1 isoforms preferentially differentiate into Tfh cells, resulting in substantially increased GC and antibody responses. This negative regulation of Foxp1 on Tfh cell differentiation shows profound dominance: even in the absence of B cells, Foxp1-deficient CD4+ T cells differentiate into Tfh cells with high frequencies and sustained Bcl6 expression. Further, in the absence of Foxp1, Tfh cells are generated in higher frequencies than seen with Bcl6 overexpression and Tfh cell differentiation becomes significantly resistant to Blimp1-mediated repression. Finally, our experiments reveal specific roles of Foxp1A and Foxp1D in inhibiting Tfh cell differentiation: TCR-induced Foxp1D functions as a M-bM-^@M-^XgatekeeperM-bM-^@M-^Y to block the initial Tfh cell development, and together Foxp1A and Foxp1D proteins inversely determine Tfh cell generation in a dosage-dependent manner. Our study suggests that two Foxp1 isoforms provide a M-bM-^@M-^\double checkM-bM-^@M-^] mechanism as fundamental regulators in Tfh cell differentiation and humoral responses. Gene expression analysis of ex vivo OT-II Foxp1-WT Tfh cells and OT-II Foxp-conditional knockout (CKO) Tfh cells 5 days after immunization.

2014-05-18 | E-GEOD-50725 | 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 [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

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

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

Expression Data from in vivo Tfh vs GC Tfh vs non-Tfh

Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo polyclonal GC Tfh vs Tfh vs Non-Tfh eight days after LCMV viral infection. Analysis of in vivo follicular helper CD4 T cells (CXCR5high GL7low), versus germinal center follicular helper CD4 T cells (CXCR5hi GL7hi), versus non-follicular helper CD4 T cells (CXCR5low) eight days after viral infection.

2010-04-28 | E-GEOD-21380 | biostudies-arrayexpress

ICOS-mediated inactivation of the FOXO1 transcription factor in the differentiation of T follicular helper cells

Project description:T follicular helper (Tfh) cells constitute an essential cell type in the induction of antibodies. We report that CD4 T cells lacking Foxo1 almost uniformly became CXCR5int Tfh cells following immunization. Moreover, a Foxo1 loss-of-function complemented an Icos mutation allowing the appearance of Tfh cells along with follicular, class-switched B cells and IgG isotype anti-DNA antibodies. Similarly, FOXO1 deficient Tfh differentiation displayed a substantially reduced dependence on ICOSL. Functional and molecular analyses show that FOXO1 regulates Tfh differentiation through a broad program of gene expression exemplified by positive regulation of Icos and negative regulation of Bcl6. These results demonstrate that a key step in Tfh differentiation is the ICOS-initiated activation of the PI3K-AKT pathway resulting in the inactivation of FOXO1. Performed ChIP-seq analysis to examine the role of foxo1 in the development of Tfh cells

2013-06-01 | E-GEOD-46525 | biostudies-arrayexpress

Early T-helper 1 Differentiation Is Marked by A Follicular Helper-like Transition: Differential Roles of STAT4 and T-bet

Project description:Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we show IL-12 acting via signal transducer and activator of transcription 4 (STAT4) induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced T-bet. Using ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh-like phenotype in the late phase of Th1 specification. Finally, Tfh-like T cells were rapidly generated following Toxoplasma gondii infection in mice, but T-bet constrained Tfh cells expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh functionalities, promoting full Th1 differentiation. The roles of STAT4 and T-bet to determine T helper cell fate were investigated by comparing DNA binding profiles of STAT4 and T-bet in Th1 conditions. The functional outcome was further evaluated by profiling DNase hypersensitivity sites and histone epigenetic marks between WT and STAT4-deficient or T-bet-deficient T cells in Th1 conditions.

2011-12-27 | E-GEOD-33802 | biostudies-arrayexpress

Quantitative Analysis of Global Proteome and Lysine Acetylome for Human CD4+ T Follicular Helper Cells

Project description:Follicular helper T (Tfh) are a subset of CD4+ T helper cells that provide help to germinal center B cells and mediate the development of long-lived humoral immunity. Tfh cells dysregulation is associated with several major autoimmune diseases. Although recent studies showed Tfh cells differentiation is controlled by the transcription factor Bcl6, cytokines and cell-cell signals, limited information is available on the proteome and post-translational modifications (PTM) of proteins in human Tfh cells. In this study, using TMT labeling technique, antibody-based affinity enrichment and high-resolution LC-MS/MS analysis, we investigated quantitative proteome and acetylome in human naive CD4+ T cells and in vitro induced Tfh (iTfh) cells. In total, we identified 802 up-regulated proteins and 598 down-regulated proteins at the threshold of 1.5 folds in iTfh cells compared to naive CD4+ T cells. With the aid of intensive bioinformatics, biological process, cellular compartment, molecular function, KEGG pathway and protein-protein interaction of these differentially expressed proteins were revealed. Moreover, our acetylome data showed that 22 lysine acetylated proteins are up-regulated and 26 lysine acetylated proteins are down-regulated in iTfh cells compared to the naive CD4+ T cells, among which 11 differentially acetylated lysine residues in core histone were identified, indicating proteins acetylation and epigenetic mechanism are involved in regulating Tfh cells differentiation. These data provide a significant resource for studies of Tfh differentiation and normal and perturbed Tfh cell function.

2021-03-19 | PXD008563 | Pride

Early T-helper 1 Differentiation Is Marked by A Follicular Helper-like Transition: Differential Roles of STAT4 and T-bet

2011-12-27 | GSE33802 | GEO

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