T cell responses of ALS patients
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PROVIDER: EGAS00001006675 | EGA |
REPOSITORIES: EGA
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Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.
2009-09-15 | E-GEOD-16210 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ Treg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promotes Treg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven Treg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident Treg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.
2024-01-24 | PXD048248 | Pride
Project description:<p>PD-1 is an important immune checkpoint inhibitor that shows great promise in the clinic, particularly for melanoma and lung cancers. Since PD-1 is also expressed on infiltrating CD4+ Treg and Teffector cells in glioblastoma, we sought to better understand the role of PD-1 on these infiltrating CD4+ Treg and Teffector cells. To this end, we performed functional and transcriptional profiling using CD4+ Treg and Teffector cells isolated from healthy donors and glioblastoma patients (from both tumors and blood).</p>
| phs001079 | dbGaP
Project description:Regulatory T cells (Treg) contribute to the crucial immunological processes of self-tolerance and immune homeostasis. However, the mechanisms underlying Treg function and cell fate decisions to differentiate between Treg and conventional T cells (Tconv) remain to be fully elucidated, especially at the histone modification level. Covalent modifications of histones establish and maintain chromatin structure, and regulate gene transcription events by facilitating access to cis-elements by trans-acting factors during mammalian development and cellular differentiation. We aimed to investigate the role of the methylation form of histone modification as related to Treg function and phenotype. High-resolution maps of the genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 were generated for human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) by sequencing using the Solexa 1G Genetic Analyzer. We found 2115 H3K4me3 regions corresponding to proximal promoter regions; the genes associated with these regions in Treg cells included the crucial transcription factor forkhead box P3 (FOXP3) and the chemokine receptor CCR7. We also identified 41024 Treg cell type-specific H3K4me1 regions. The majority of the H3K4me1 regions differing between the Treg and aTconv cells were located at promoter-distal sites, some of which were selected and consolidated to further examine enhancer activity in in vitro reporter gene assays. The findings from our study provide a comprehensive genome-wide dataset of lineage-specific H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control the differentiation decision, lineage commitment and cell type-specific gene regulation. This basic principle is likely not confined to the two closely-related T cell populations, but may apply generally to somatic cell lineages in adult organisms. Genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 in human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) (5 samples in total)
2011-01-31 | E-GEOD-26427 | biostudies-arrayexpress
Project description:By restraining T cell activation and promoting regulatory T cell (Treg) expansion, myeloid-derived suppressor cells (MDSC) and tolerogenic dendritic cells (DC) (tDC) can control self-reactive and anti-graft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor-free donors. In the present study we describe and characterize a novel population of myeloid suppressor cells, named fibrocytic MDSC (f-MDSC), that are differentiated from umbilical cord blood (UCB) precursors by a 4 day culture with FDA approved cytokines (rh-GM-CSF and rh-G-CSF). This MDSC subset, characterized by the expression of MDSC-, DC-, and fybrocyte-s associated markers, promotes Treg regulatory cells expansion and promote normoglycemia in a xenogeneic model of Type 1 Diabetes (T1D). In order to exert their pro-tolerogenic function, fibrocytic MDSC require direct contact with activated T cells, which leads to the induction and secretion of indoleamine 2,3 deoxygenase (IDO). This new myeloid subset may represent an important tool for the in vitro and in vivo production of Treg for the treatment of autoimmune diseases, and either prevention or control of allograft rejection. Keywords: expression profiling by array Human Umbilical cord blood (UCB) samples were cultured for 4 days with GM-CSF and G-CSF after Ficoll-Paque gradient separation and red cell lysis. CD33+/IL-4RM-NM-1+ cells were sterilely sorted and part stored in Trizol for RNA extraction (BEFORE CONTACT), and part co-cultured with autologous PHA activated CD3+ T cells either in cell to cell contact (CONTACT) or using a transwell device to separate the two popyulations (TRANSWELL). Three days later, T cells were removed from the co-culture either by repeated washes with PBS or by simply removing the transwell device. Adherent cells were lysed with Trizol and stored at -80M-bM-^@M-^YC. RNA extraction was carry on with miRNAeasy mini kit from Quiagen; RNA QC was assessed by Agilent BioAnalyzer 6000 and samples were analyzed with Affymetrix Human 2.0 ST array
2014-08-26 | E-GEOD-52376 | biostudies-arrayexpress
Project description:Regulatory T cells (Treg) have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to meet increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and, in addition, the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. Foxp3 also imparts a selective advantage in ATP generation capacity, one that might be exploited as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing CD4+ T cells from various sources with Foxp3- activated CD4 T cells, as well as Treg from human peripheral blood. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 expression is associated with a significant up regulation of several members of the mitochondrial electron transport chain. Not only does Foxp3 influence genes directly concerned with immune function, but also with the energy generating functions of Treg.
2017-02-15 | PXD001906 | Pride
Project description:Induced and activated regulatory CD4+ Foxp3+ cells compared Conventional naive CD4+ T cells were sorted and converted in vitro into adaptive Treg cells, activated Treg cells were generated in vitro from sorted Foxp3GFP+ cells
2012-01-18 | E-GEOD-28130 | biostudies-arrayexpress
Project description:Using single-cell RNA sequencing (10X technology) on CD4+T cells, we report that GM-CSF-activated human blood CD1c+ dendritic cells (DC) (cDC2) drive the differentiation of naïve CD4+ T cells into Tfh1. These Tfh1 cells displayed typical Tfh molecular features, including high levels of PD-1, CXCR5, and ICOS. They co-expressed Bcl6 and T-bet, and secreted large amounts of IL-21 and IFN-γ.
2022-10-01 | GSE167364 | GEO
Project description:The CD4+ regulatory T (Treg) cell lineage comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. As a model for Treg cells, studies employ TGF-β-induced (i)Treg cells generated from CD4+ conventional T (Tconv) cells in vitro. Here, we describe the relationship of iTreg cells to tTreg and Tconv cells. Proteomic analysis revealed that iTreg, tTreg and Tconv cell populations each have a unique protein expression pattern. iTreg cells had very limited overlap in protein expression with tTreg cells, regardless of cell activation status and instead shared signaling and metabolic proteins with Tconv cells. tTreg cells had a uniquely modest response to CD3/CD28-mediated stimulation. As a benchmark, we used a previously defined proteomic signature that sets ex vivo naïve and effector phenotype Treg cells apart from Tconv cells and includes unique Treg cell properties (Cuadrado et al., Immunity, 2018). This Treg cell core signature was largely absent in iTreg cells. We also used a proteomic signature that distinguishes ex vivo effector Treg cells from Tconv cells and naïve Treg cells. This effector Treg cell signature was partially present in iTreg cells. In conclusion, iTreg cells are distinct from tTreg cells and share limited features with ex vivo Treg cells at the proteomic level.
2022-11-28 | PXD038302 | Pride
Project description:Regulatory T cell (Treg) impairment is a common denominator of autoimmune pathologies. Despite the extensive characterization of Treg cell phenotype in autoimmunity, the molecular mechanisms underlying their deterioration remain ill defined. To investigate Treg dysfunction during autoimmunity we performed transcriptomic analysis of CD4+CD25highCD127- Treg cells from peripheral blood of patients with autoimmunity.
| EGAS00001004470 | EGA