CD4+ T cell activation in absence of WNK1
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201228 | GEO | 2024/12/03
REPOSITORIES: GEO
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Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).
2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress
Project description:CD4 CD8 double positive (DP) thymocytes progressively shut down Notch signaling after β-selection allowing progression of the DP program and positive selection of conventional CD4 and CD8 single positive T cells. In contrast, innate CD8+ T cells are selected from DP precursors shortly after β-selection. Here, we investigated whether notch signaling is required for the initiation of the innate T cell developmental program upon TCR engagement. We show that, after β-selection, Notch activation limits progression to late DP cells and favors the development of TCRαβ/CD3 expressing CD8dim early DP progenitors. TCR engagement in these Notch dependent TCRαβ+ early DP precursors does not induce prominent apoptosis, but rather induces T-bet expression by an mTOR-dependent mechanism. Our findings indicate that Notch signaling drives the launch of an innate effector program in response to TCR agonist selection in the thymus.
2019-09-05 | GSE100519 | GEO
Project description:CD4+ T cells have a central role in controlling Mtb infection (1). Despite immune control, Mtb persists by interfering with macrophage and T cell function, allowing for pathogen survival. Our group has demonstrated direct and indirect inhibition of CD4+ T cell activation by different Mtb molecules including lipoproteins LpqH, LprA and LprG, and ManLAM (2-5). ManLAM is an abundant glycolipid in the Mtb cell wall and interferes with TCR signaling by down-regulating phosphorylation of Lck, CD3, ZAP70 and LAT (6). Activation through the TCR-CD3 complex leads to marked changes in the proteome of T cells. Entry into cell cycle, production of cytokines and differentiation from naïve to effector and memory T cell are all reflected in the production and modification of multiple proteins. Mass spectrometry (MS) has been used to characterize TCR complex formation (7-11) and the effect of a range of stressors on the T cell proteome (12-14). Recent advances have overcome technical issues in quantitative MS and allow analysis of the complexity and dynamic range of the cellular proteome (15). To extract biological meaning different bioinformatic tools have been developed for MS based cellular studies (16, 17). In this study we used label-free quantitative MS to characterize the effect of ManLAM on the proteome of activated CD4+ T cells. Approximately 5000 peptides were identified and quantitated from three biological experimental datasets in primary murine CD4+ T cells treated with or without ManLAM and activated with anti-CD3 and anti-CD28 monoclonal antibodies (mAb). Peptides with varying abundance were selected by likelihood ratio based statistical significance by comparing the intensities under different experimental conditions. ManLAM treatment resulted in abundance changes for 149 peptides representing 131 proteins in the activated CD4+ T cell proteome that affected a variety of enriched cluster modules and pathways. Validation experiments confirmed Man LAM induced inhibition of Proliferating Cell Nuclear Antigen (PCNA) that regulates cell cycle progression. Protein-protein interaction (PPI) network analysis revealed a central role for the Akt/mTOR signaling pathway. WB studies revealed decreased phosphorylation of both Akt and mTOR in ManLAM treated CD4+ T cells as well as decreased expression of Otub1, a key molecule regulated by mTOR. Thus disruption of the activated CD4+ T cell proteome by ManLAM-mediated inhibition of proximal TCR signaling is primarily mediated through inhibition of Akt-mTOR signaling.
2018-07-05 | PXD004164 | Pride
Project description:T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4 T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca2+ levels and regulated via N-Wasp and NIK. Specific interference with TCR-induced formation of nuclear actin filaments impairs production of effector cytokines and prevents generation of antigen-specific antibodies, but does not interfere with immune synapse formation and cell proliferation. Ca2+-regulated actin polymerization in the nucleus allows CD4 T cells the rapid conversion of TCR signals into effector functions required for T cell help Identification of nuclear F-actin sensitive genes upon TCR signaling
2018-11-15 | GSE122531 | GEO
Project description:T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular calcium (Ca2+) to activate the key transcription factors NFAT and NF-κB. The mechanism of NFAT activation by Ca2+ has been determined; however, the role of Ca2+ in controlling NF-κB signaling is poorly understood and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF- induced NF-κB signaling upstream of IκB kinase (IKK) activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent CRAC/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser536 and that this post- translational modification controls its nuclear localization and transcriptional activation. Notably our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκBα degradation, thereby identifying a novel Ca2+- dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKCk-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR induced NF-kB activation and we define a new distal Ca2+-dependent checkpoint in TCR-induced NF-kB signaling that has broad implications for the control of immune cell development and T cell functional specificity. 3 treatments were analyzed, with biological replicates for each treatment. In addition, three timepoints (1 hour, 4 hour, and 8 hour) were examined for each treatment, as well as an untreated control. In total 19 samples were analyzed
2016-01-14 | E-GEOD-76804 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) suppress other immune cells and are indispensable for human health, yet the molecular mechanisms of suppression remain incompletely understood. Tregs can suppress proliferation and cytokine production of CD4+CD25- conventional T cells (Tcons). We previously demonstrated that human Tregs rapidly suppress T cell receptor (TCR)-induced calcium, NFAT and NF-κB pathways in Tcons, leading to inhibition of effector cytokine transcription (Schmidt A et al., Science Signaling 2011 Dec 20;4(204):ra90. doi: 10.1126/scisignal.2002179). Due to the short time period required to induce suppression, it is probable that Tregs alter protein modifications, such as (de)phosphorylations, in suppressed Tcons to cause this inhibition of particular TCR signaling events, while de novo production of repressor proteins seems unlikely. Thus, in order to identify causative factors which initiate rapid Treg-mediated suppression of Tcons, we compared phosphoproteomes of 5 minutes TCR-stimulated responder Tcons re-isolated from cocultures with primary human Tregs with those from control cocultures (Tcons cocultured with other Tcons). In addition, we measured the basal state of the phosphoproteome in unstimulated Tcon of the same donors. In total, we provide phosphoproteomics data of primary human CD4+CD25- T cells from three human healthy donors each for (i) unstimulated Tcons, (ii) 5 minutes TCR-stimulated Tcons, (iii) 5 minutes TCR-stimulated and Treg-suppressed Tcons.
2017-08-28 | PXD004291 | Pride
Project description:CD4+ T cell activation in absence of WNK1
| PRJNA830460 | ENA
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.
2010-04-28 | E-GEOD-21379 | biostudies-arrayexpress
Project description:Title of Publication: Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes Abstract of publicaton: CD4/CD8 double-positive (DP) thymocytes express the transcriptional repressor Histone Deacetylase 7 (HDAC7), a class IIa HDAC that is exported from the cell nucleus after T cell receptor (TCR) engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in thymocytes, and regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR J segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAP kinase activity that contributes to the observed loss of viability. Remarkably, the activity of Protein Kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining auto-excitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. Goal of Microarray experiment: We did these experiments to determine how alteration of the function of HDAC7, a site-specific and signal-dependent repressor of transcription, changes gene expression in CD4/CD8 DP thymocytes. Three biological replicate samples were prepared for each non-wild type mouse strain (Samples 7-18). Six biological replicates were prepared for the wild type strain (Samples 1-6). Total RNA was prepared from isolated CD4/CD8 Double-positive thymocytes and labeled with the Affymetrix Whole-Transcript labeling protocol. Labeled probes were hybridized to one Affymetrix Mouse Gene 1.0ST array each. Data from .cel files were normalized using RMA, in normalization groups representing each of the binary comparisons made. These binary comparisons between sample groups represent gene expression changes due to loss of HDAC7 (samples 1-3 vs. 7-9), transgenic expression of an HDAC7-VP16 fusion protein (samples 4-6 vs. 10-12), positive thymic selection (samples 1-6 vs. samples 11-15), and negative thymic selection (Samples 11-15 vs. samples 16-18).
2011-04-06 | E-GEOD-26488 | biostudies-arrayexpress
Project description:CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.
2021-04-06 | MODEL1903260003 | BioModels