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Whole-transcriptome quantitative analysis of WT versus Ikzf3-/- CD4+ T cells cultured in Th1-polarizing or Tfh-polarizing conditions

ABSTRACT: Effective immunity to viruses such as influenza and SARS-CoV-2 requires the generation of CD4+ T cell subsets that coordinate complementary aspects of the immune response. These include T follicular helper (TFH) and T helper 1 (TH1) cells, which promote humoral and cell-mediated helper responses, respectively. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs) facilitates clearance of infection via mechanisms normally associated with CD8+ T cells, including perforin-mediated destruction of infected cells. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL responses. We demonstrate that Aiolos deficiency compromises TFH differentiation and antibody production during influenza infection. Conversely, we find that CD4+ T cells acquire a cytotoxic-like program in the absence of Aiolos, including increased expression of the CTL-associated transcription factors Eomes and Blimp-1. We further show that while Aiolos positively regulates the TFH transcriptional regulators Zfp831, Tcf-1 and Bcl-6, it also directly represses expression of IL-2Ra and IL-2/STAT5-driven expression of the cytotoxic gene program. Thus, our findings identify Aiolos as a pivotal regulator of TFH and CD4-CTL differentiation and highlight its potential as a therapeutic target for the manipulation of CD4+ T cell humoral and cytotoxic responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE203065 | GEO | 2023/02/01

REPOSITORIES: GEO

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ATAC-seq analysis of WT versus Ikzf3-/- CD4+ T cells cultured in Th1-polarizing or Tfh-polarizing conditions

Project description:Effective immunity to viruses such as influenza and SARS-CoV-2 requires the generation of CD4+ T cell subsets that coordinate complementary aspects of the immune response. These include T follicular helper (TFH) and T helper 1 (TH1) cells, which promote humoral and cell-mediated helper responses, respectively. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs) facilitates clearance of infection via mechanisms normally associated with CD8+ T cells, including perforin-mediated destruction of infected cells. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL responses. We demonstrate that Aiolos deficiency compromises TFH differentiation and antibody production during influenza infection. Conversely, we find that CD4+ T cells acquire a cytotoxic-like program in the absence of Aiolos, including increased expression of the CTL-associated transcription factors Eomes and Blimp-1. We further show that while Aiolos positively regulates the TFH transcriptional regulators Zfp831, Tcf-1 and Bcl-6, it also directly represses expression of IL-2Ra and IL-2/STAT5-driven expression of the cytotoxic gene program. Thus, our findings identify Aiolos as a pivotal regulator of TFH and CD4-CTL differentiation and highlight its potential as a therapeutic target for the manipulation of CD4+ T cell humoral and cytotoxic responses.

2023-02-01 | GSE203064 | GEO

Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19

Project description:The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present a large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T helper (TH)1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide so far unprecedented insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities.

2020-10-06 | GSE152522 | GEO

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

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

Regulation of Tfh differentiation by Mettl3 [RNA-seq]

Project description:T follicular helper (Tfh) cells are a specialized subset of CD4 T cells that are essential for most antibody productions and humoral responses. It is well characterized that transcriptional network exerts indispensable roles in Tfh cell differentiation. However, how post-transcriptional regulation controls Tfh biology has largely remained unclear. Multiple mice models were used here by a series of experimental approaches to illustrate m6A methyltransferase Mettl3 programs Tfh cell differentiation at post-transcriptional layer.

2021-01-19 | GSE129648 | GEO

CD4+ follicular regulatory T cells optimize the influenza virus-specific B cell response

Project description:CD4+ follicular regulatory T cells (Tfr cells) control B cell responses through the modulation of follicular helper T (Tfh) cells and germinal center development, while suppressing autoreactivity; however, their role in the regulation of productive germinal center B cell responses and humoral memory is incompletely defined. We show that Tfr cells promote antigen-specific germinal center B cell responses upon influenza virus infection. Following viral challenge, we found that Tfr cells are necessary for robust generation of virus-specific, long-lived plasma cells, antibody production against both hemagglutinin (HA) and neuraminidase (NA), the two major influenza virus glycoproteins, and appropriate regulation of the BCR repertoire. To further investigate the functional relevance of Tfr cells during viral challenge, we utilized a sequential immunization model with repeated exposure of antigenically partially conserved strains of influenza viruses, revealing that Tfr cells promote recall antibody responses against the conserved HA stalk region. Thus, Tfr cells promote antigen-specific B cell responses and are essential for the development of long-term humoral memory.

2020-11-20 | GSE161788 | 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. Naïve 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 ‘gatekeeper’ 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 “double check” mechanism as fundamental regulators in Tfh cell differentiation and humoral responses.

2014-05-18 | GSE50725 | GEO

Transcriptional profiling for lung tissue-resident helper T cell and spleen follicular T cells

Project description:We reported hybrid CD4+ T cell population following influenza viru infection. The hybrid CD4+ T cells exhibit both tissue residency and follicular helper T cell features. To further charaterization, we sorted lung tissue-resident helper T (TRH or TTH) cells (CD45iv-CD4+CD44+GITR-PD1hiFR4hi), non-TRH (CD45iv-CD4+CD44+GITR-PD1lowFR4low), spleen follicalar helper T (TFH) cells (CD4+CD44+GITR-PD1hiCXCR5hi) and non-TFH cells (CD4+CD44+GITR-PD1lowCXCR5low). Then the cells were applied for RNA sequencing. At the resut, we showed tissue-residency related genes are highly enriched in lung TRH but not spleen TFH cells. And The lung TRH cells express higher levels of TFH-related genes than lung-non TRH cells. Therefore, we suggest TRH cells play a role as tissue-resident helper T cells.

2020-11-27 | GSE153226 | GEO

Transcriptional analysis of human blood CXCR5+ CD4 T cell populations

Project description:The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. Generation of long term humoral immunity is a complex process predominantly dependent on germinal centers and CD4 T cell help to B cells. Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help. However, whether such cells develop memory in humans and can be tracked in human blood has been enigmatic. We identified a subpopulation of blood CXCR5+ PD-1+CXCR3- resting CD4 T cells that are most related to Tfh cells of lymphoid tissue by gene expression profile and phenotype. Functional analysis showed that these memory Tfh cells were specialized for helping B cells. Moreover, these cells correlate with a clinically important outcome: development of potent neutralizing antibodies against HIV in HIV+ individuals. CD4 T cells were enriched from fresh blood of 5 normal donors by magnetic beads negative selection. Following enrichment, CD14-CD16-CD19-CD8-CD4+CD45RA- cells from each donor were FACS sorted into the following 5 populations: CXCR5-, CXCR5+PD1+CXCR3-, CXCR5+PD1+CXCR3+, CXCR5+PD1-CXCR3-, and CXCR5+PD1-CXCR3+. The gene expression profile of each cell population was determined.

2013-11-12 | E-GEOD-50390 | biostudies-arrayexpress

Human Extrafollicular CD4+ T Helper Cells Help Memory B Cells Produce Immunoglobulins

Project description:Follicular helper T (Tfh) cells are necessary for germinal center B cell maturation during primary immune responses; however, the T cells that promote humoral recall responses via memory B cells are less well defined. We herein characterize a human tonsillar CD4+ T cell subset with this function. These cells are similar to Tfh cells in terms of expression of the chemokine receptor CXCR5 and the inhibitory receptor PD-1, interleukin (IL)-21 secretion, and expression of the transcription factor BCL6; however, unlike Tfh cells that are located within the B cell follicle and germinal center, they reside at the border of the T cell zone and the B cell follicle in proximity to memory B cells, a position dictated by their unique chemokine receptor expression. They promote memory B cells to produce antibodies via CD40 ligand, IL-10, and IL-21. Our results reveal a unique extrafollicular CD4+ T cell subset in human tonsils, which specialize in promoting T cell-dependent humoral recall responses.

2018-06-29 | GSE52156 | GEO

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