Translational regulation of T follicular helper cell differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE193652 | GEO | 2022/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:Regulatory T cells expressing the transcription factor Foxp3 play indispensable roles for the induction and maintenance of immunological self-tolerance and immune homeostasis. Genome-wide mRNA expression-studies have defined canonical signatures of T-cell subsets. Changes in steady-state mRNA levels do, however, often not reflect those of corresponding proteins due to post-transcriptional mechanisms including mRNA translation. Here, we unveil a unique translational signature, contrasting CD4+Foxp3+ regulatory T (TFoxp3+) and CD4+Foxp3- non-regulatory T (TFoxp3-) cells, which imprints subset-specific protein expression. We further show that translation of eukaryotic translation initiation factor 4E (eIF4E) is induced during T-cell activation and, in turn, regulates translation of cell cycle related mRNAs and proliferation in both TFoxp3- and TFoxp3+ cells. Unexpectedly, eIF4E also affects Foxp3 expression and thereby lineage identity. Thus, mRNA-specific translational control directs both common and distinct cellular processes in CD4+ T-cell subset. CD4+/Foxp3+ and CD4+Foxp3- cells were studied ex vivo or activated in vitro for 36h. Both polysome-associated and cytoplasmic RNA was isolated to enables studies of translational control
2013-06-01 | E-GEOD-45401 | biostudies-arrayexpress
Project description:Regulatory T cells expressing the transcription factor Foxp3 play indispensable roles for the induction and maintenance of immunological self-tolerance and immune homeostasis. Genome-wide mRNA expression-studies have defined canonical signatures of T-cell subsets. Changes in steady-state mRNA levels do, however, often not reflect those of corresponding proteins due to post-transcriptional mechanisms including mRNA translation. Here, we unveil a unique translational signature, contrasting CD4+Foxp3+ regulatory T (TFoxp3+) and CD4+Foxp3- non-regulatory T (TFoxp3-) cells, which imprints subset-specific protein expression. We further show that translation of eukaryotic translation initiation factor 4E (eIF4E) is induced during T-cell activation and, in turn, regulates translation of cell cycle related mRNAs and proliferation in both TFoxp3- and TFoxp3+ cells. Unexpectedly, eIF4E also affects Foxp3 expression and thereby lineage identity. Thus, mRNA-specific translational control directs both common and distinct cellular processes in CD4+ T-cell subset.
2013-06-01 | GSE45401 | GEO
Project description:T follicular helper CD4 T cells (Tfh) provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike blood, we consistently identified a CXCR5-Bright PD-1-Bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh, and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.
2019-07-01 | GSE130793 | GEO
Project description:T follicular helper CD4 T cells (Tfh) provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike blood, we consistently identified a CXCR5-Bright PD-1-Bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh, and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.
2019-07-01 | GSE130791 | 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.
2021-03-19 | PXD008563 | Pride
Project description:Using mRNA-seq and ChIP-seq in muscle tissue, we found that BCL6 controls a broad range of anabolic targets, directly suppressing eukaryotic translation initiation factor 4E-binding protein 1 (Eif4epb1) and myostatin (Mstn) while enhancing insulin-like growth factor 1 (Igf1) and androgen receptor (Ar). Consistent with these gene regulatory effects, skeletal muscle ablation of Bcl6 increased physical association of the translation initiation factor eIF4E with its inhibitor EIF4E-BP1 and ribosomal sequencing in vivo revealed reduced translation efficiency.
2023-12-26 | GSE190956 | GEO
Project description:Transcriptional events leading to outgrowth of neuronal axons have been intensively studied, but the role of translational regulation in this process is not well understood. Here we use translatome analyses by ribosome pull-down and protein synthesis characterization by metabolic isotopic labeling to study nerve injury and axon outgrowth proteomes in rodent dorsal root ganglia (DRG) and sensory neurons. We identify over 1600 gene products that are primarily translationally regulated in DRG neurons after nerve injury, many of which contain a 5’UTR CERT motif, implicating the translation initiation factor Eif4e in the injury response. We further identified approximately 200 proteins that undergo robust de novo synthesis in the initial stages of axon growth. ApoE is one of the highly synthesized proteins in neurons, and inhibition of its signaling affects axon outgrowth. These findings suggest prominent roles for translational regulation in initial stages of the neuronal injury response and axon extension.
2018-04-25 | GSE102316 | GEO
Project description:Aberrant activation of the translation initiation machinery is a common property of malignant cells, and is essential for breast carcinoma cells to manifest a malignant phenotype. How does sustained activation of the rate limiting step in protein synthesis so fundamentally alter a cell? In this report, we test the post transcriptional operon theory as a possible mechanism, employing a model system in which apoptosis resistance is conferred on NIH 3T3 cells by ectopic expression of eIF4E. We show (i) there is a set of 255 transcripts that manifest an increase in translational efficiency during eIF4E-mediated escape from apoptosis; (ii) there is a novel prototype 55 nt RNA consensus hairpin structure that is overrepresented in the 5'-untranslated region of translationally activated transcripts; (iii) the identified consensus hairpin structure is sufficient to target a reporter mRNA for translational activation under pro-apoptotic stress, but only when eIF4E is deregulated; and (iv) that osteopontin, one of the translationally activated transcripts harboring the identified consensus hairpin structure functions as one mediator of the apoptosis resistance seen in our model. Our findings offer genome-wide insights into the mechanism of eIF4E-mediated apoptosis resistance and provide a paradigm for the systematic study of posttranscriptional control in normal biology and disease. To globally address the issue of which transcripts mediate the anti-apoptotic functions of eIF4E, we used a model in which NIH 3T3 cells ectopically overexpress translation initiation factor 4E (eIF4E) resulting in an apoptosis-resistant and tumorigenic phenotype. We performed a comprehensive study of apoptosis resistance in the NIH 3T3/4E model using an array containing 15k cDNAs and ESTs (NIH 15k collection printed at The Ontario Cancer Institute). To facilitate data analysis in the two-color competitive hybridization microarray approach employed, we used a universal standard mRNA [non-stratified poly(A) selected RNA derived from NIH 3T3 cells cultured in full growth medium]. We compared signals generated from this standard to both the light (fractions 4â6, <1 ribosome/transcript) and the heavy (fractions 7â10, >1 ribosomes/transcript) polyribosome fractions of RNA from NIH 3T3 and NIH 3T3/4E cells cultured either in complete growth medium or after 16 h of serum starvation, a time point before any evidence of cytochrome c release from the mitochondria, a signature step at the apex of the cell death program. We selected the 16 h time point in order to identify genes that might govern the decision to enter the apoptotic pathway, and exclude those involved in the actual process of cell execution.
2010-06-10 | E-GEOD-2094 | biostudies-arrayexpress
Project description:DUX4, an embryonic transcription factor normally silenced in somatic tissues, was recently shown to reduce major histocompatibility complex I (MHC-I) and promote immune evasion in numerous cancer types. We report that transient expression of DUX4 results in the long-term suppression of interferon-gamma induction of MHC-I and the immunoproteasome. Brief expression of transcriptionally active DUX4 leads to a prolonged decrease in protein synthesis, altering the activity of translation initiation regulators eIF2a, eIF4E, 4EBP1, and translation elongation factor eEF2. Translational profiling identified mRNAs susceptible to DUX4-induced inhibition of translation initiation and elongation, including mRNAs encoding antigen presentation factors. We show that DUX4 orchestrates translational reprogramming by broadly attenuating protein synthesis while inducing the expression of RNAs encoding early embryonic proteins that are translationally up regulated and predicted to be less vulnerable to translational inhibition. Endogenous expression of DUX4 and its target genes in FSHD muscle cells and SuSa germinoma cells also correlates with suppression of protein synthesis and reduced MHC-I presentation. Our findings reveal a novel role of DUX4 in modulating translational control to reshape the cellular translatome with important implications for development and disease.
2023-02-01 | GSE206437 | GEO
Project description:DUX4, an embryonic transcription factor normally silenced in somatic tissues, was recently shown to reduce major histocompatibility complex I (MHC-I) and promote immune evasion in numerous cancer types. We report that transient expression of DUX4 results in the long-term suppression of interferon-gamma induction of MHC-I and the immunoproteasome. Brief expression of transcriptionally active DUX4 leads to a prolonged decrease in protein synthesis, altering the activity of translation initiation regulators eIF2a, eIF4E, 4EBP1, and translation elongation factor eEF2. Translational profiling identified mRNAs susceptible to DUX4-induced inhibition of translation initiation and elongation, including mRNAs encoding antigen presentation factors. We show that DUX4 orchestrates translational reprogramming by broadly attenuating protein synthesis while inducing the expression of RNAs encoding early embryonic proteins that are translationally up regulated and predicted to be less vulnerable to translational inhibition. Endogenous expression of DUX4 and its target genes in FSHD muscle cells and SuSa germinoma cells also correlates with suppression of protein synthesis and reduced MHC-I presentation. Our findings reveal a novel role of DUX4 in modulating translational control to reshape the cellular translatome with important implications for development and disease.
2023-02-01 | GSE206438 | GEO