Murine follicular helper T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201242 | GEO | 2022/06/06
REPOSITORIES: GEO
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2021-09-01 | GSE157648 | GEO
Project description:T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding the nature of the cDC responsible for instructing Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist, in part, due to the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that we show delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different formulations of antigen delivery, we determined that CD11b+ migratory type 2 conventional DCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2 but not CD103+ cDC1 migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell and antibody development, whereas loss of CD103+ cDC1s in Batf3-/- mice did not. Loss of cDC2-mediated Tfh responses was associated with impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the sub-anatomic regions of the lymph node where Tfh cell priming occurs, the T-B border. This work identifies the DC responsible for Tfh cell-dependent antibody responses, in particular when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.
2017-12-01 | GSE103956 | GEO
Project description:Loss of Elp3 in CD4 T cells hindered the development of an optimal T follicular helper T cell (TFH) response. To understand the molecular pathway by which Elp3 is necessary for TFH responses, mice deficient for Elp3 in T cells and WT littermate were immunized with ovalbumin emulsified with complete Freund Adjuvant. 8 days later, TFH were sorted from the draining lymph nodes and submitted for RNAseq
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Project description:Despite interest in T follicular helper (TFH) cell development and function, differences between TFH cells resident in germinal centers (GCs) and phenotypically similar, non-resident TFH cells are unclear. Both TFH subsets share the Bcl6+FoxP3−CXCR5hiPD-1hi phenotype but we show that only GC resident TFH cells express S1pr2 and lose CD90 expression. Whereas immunization elicits CD90neg/lo GCTFH and CD90hi GCTFH-like cells similarly, these TFH subsets have distinct properties. CD90neg/lo GCTFH cells require MHCII+ B cells to develop and once formed, do not proliferate. CD90hi GCTFH-like cells are generated in the absence of B cells and remain mitotically active. The Tcrβ repertoires of both TFH types are initially shared but with time, Tcrβ usage in CD90hi GCTFH-like cells substantially diverges by DC-driven proliferation. Transcriptome analysis shows CD90neg/lo GCTFH to be specialized for vesicle transport and exocytosis while gene expression in CD90hi GCTFH-like cells is linked to cell activation, proliferation and migration.
2020-03-17 | GSE147035 | GEO
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.
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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 antigen-specific (LCMV-specific, SMARTA TCR transgenic) WT and Sh2d1a-/- follicular helper CD4 T cells (CXCR5high),versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection.
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Project description:Splenic innate-like marginal zone B (MZB) cells are strategically positioned at the interface between the circulating blood and lymphoid tissue, where they initiate rapid immune responses to blood-borne antigens. Here, we find that selective genetic deletion of MZB cells substantially increases the follicular helper T (Tfh) cell and germinal center (GC) response to high cholesterol diet (HCD), which leads to T cell-dependent acceleration of atherosclerosis. We show that MZB cells activate a homeostatic program in response to HCD, in which upregulation of the transcription factor Atf3 plays a determinant regulatory role. Shuttling of MZB cells to the follicle is dispensable for their regulatory properties on Tfh cells. Instead, HCD promotes increased interaction between MZB and (pre-)Tfh cells outside the follicle, and upregulates MZB cell expression of Cd274 in an Atf3-dependent manner. Interaction between MZB and Tfh cells leads to Cd274-mediated suppression of Tfh cell motility, limits Tfh cell accumulation in the follicle and suppresses the pro-atherogenic Tfh/GC response. Our findings reveal a previously unsuspected role for MZB cells in the control of Tfh/GC response to a cholesterol diet, and uncover a new mechanism through which MZB cells can couple their unique metabolic and innate immune properties and use them to maintain a tolerogenic state. The results may have broad (patho)physiological implications.
2016-12-01 | GSE71699 | GEO
Project description:T follicular helper (TFH) cells are essential for developing protective antibody responses following vaccination. Greater understanding of the genetic program leading to TFH differentiation is needed. Chromatin modifications are central in the control of gene expression. However, detailed knowledge of how chromatin regulators (CRs) regulate differentiation of TFH cells is limited. We screened a large shRNA library targeting all known CRs in mouse and identified the histone methyltransferase Mll1 as a positive regulator of TFH differentiation. Loss of Mll1 expression reduced formation of TFH cells following acute viral infection or protein immunization. In addition, expression of the TFH lineage-defining transcription factor Bcl6 was reduced in the absence of Mll1. Transcriptomics analysis identified Lef1 and Tcf7 as genes dependent on Mll1 for their expression, which provides one mechanism for the regulation of TFH differentiation by Mll1. Taken together, CRs such as Mll1 substantially influence TFH differentiation.
2023-03-21 | GSE226341 | GEO
Project description:Follicular helper T cell (Tfh) provide essential help for humoral immune response. However, how Tfh differentiation is epigenetically regulated remains incompletely understood. Here we found that H3K36me2 methyltransferase Nsd2 is required for Tfh differentiation. Lack of Nsd2 leads to reduced Tfh generation and germinal center response. Mice with Nsd2 deficiency in T cells have reduced capability of chronic virus control. To understand the molecular mechanism by which Nsd2 regulates Tfh differentiation, RNA-seq analysis of Nsd2 wildtype and knockout Tfh cells were performed.
2019-10-15 | GSE130550 | GEO
Project description:Transcriptional regulation of cell fate decisions in the immune system endows cells with specialized function; an iterative process that adapts to the changing landscape of infections. As coordinators of the immune system, T helper cells of the CD4+ lineage possess the ability to differentiate into an array of functional cell states in order to guide the response towards antibody production via the formation of T follicular helper (Tfh) cells or inflammation by the generation of T effector (Teff) cells. Tfh–Teff cell fate choice is mediated by the BCL6–Blimp-1 counter-antagonistic gene regulatory module, polarizing Tfh and Teff cells, respectively. A key question is how T helper cells establish and negotiate BCL6–Blimp-1 counter antagonism to control the output of Tfh and Teff cells. We show that the T cell receptor (TCR)-signal induced transcription factor, IRF4, is necessary for the generation of both BCL6-expressing Tfh cells and Blimp-1-expressing Teff cells. Importantly, we show that increasing TCR signal strength augments the amounts of IRF4 expressed as well as Teff cell fate trajectories that occur at the expense of Tfh cells. Using an orthogonal genetic system, based on a tet-inducible allele of Irf4, we demonstrate that increasing IRF4 expression during priming redirected Tfh cell fate choices towards those of Teff. Importantly, promotion of Teff cell fate trajectories by increased IRF4 expression occurred independently of IL-2 signals. At the molecular level, we link greater IRF4 abundance with its recruitment to low affinity DNA binding sites embedded within regulatory elements affiliated with the Teff gene program, including Blimp-1. Together, these results demonstrate that the Irf4 locus functions as the “reader” of TCR signal strength, in turn, the concentration dependent activity of the IRF4 transcription factor “writes” T helper cell fate choice.
2017-10-25 | GSE92272 | GEO