Induction of stable human FOXP3+ Tregs by a parasite-derived TGF-β mimic
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ABSTRACT:
PROVIDER: PRJNA691165 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13401502.fastq.gz | Fastqsanger.gz | |||
| SRR13401503.fastq.gz | Fastqsanger.gz | |||
| SRR13401504.fastq.gz | Fastqsanger.gz | |||
| SRR13401505.fastq.gz | Fastqsanger.gz | |||
| SRR13401506.fastq.gz | Fastqsanger.gz |
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Project description:Objectives. Immune homeostasis in the intestinal tract is tightly controlled by FOXP3+ regulatory T cells (Tregs), with loss of this Treg-mediated control linked to development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites strengthen intestinal Treg activity, leading to the notion that parasite-derived products could be harnessed and used as an immunoregulatory therapy for IBD. It has been previously demonstrated that the parasite Heligmosomoides polygyrus secretes a molecule (Hp-TGM) which mimics the ability of TGF-β to induce FOXP3 expression in CD4+ T cells. Our aim was to investigate whether Hp-TGM could induce human FOXP3+ Tregs as a potential therapeutic approach. Methods. Human CD4+ T cells from healthy volunteers were expanded in the presence of Hp-TGM or mammalian TGF-β. The induction of Tregs was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CTLA-4 and CD25. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was assessed by cellular co-culture suppression assays and secreted cytokines measured by cytometric bead array. Results. Hp-TGM efficiently induced FOXP3 expression (>60%), in addition to another Treg functional marker CTLA-4. Hp-TGM caused epigenetic modification of the FOXP3 loci to a greater extent than did TGF-β. Hp-TGM-induced Tregs also had superior suppressive function compared to TGF--induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Hp-TGM also induced a Treg phenotype in in vivo differentiated Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. Conclusion. These data indicate Hp-TGM has the potential to be used to generate stable human FOXP3+ Tregs to treat IBD.
2021-04-29 | GSE164548 | GEO
Project description:Immune homeostasis in the intestine is tightly controlled by FOXP3+ regulatory T cells (Tregs), defects of which are linked to the development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites boost Treg activity. The parasite Heligmosomoides polygyrus is known to secrete a molecule (Hp-TGM) that mimics the ability of TGF-β to induce FOXP3 expression in CD4+ T cells. The study aimed to investigate whether Hp-TGM could induce human FOXP3+ Tregs as a potential therapeutic approach for inflammatory diseases. CD4+ T cells from healthy volunteers were expanded in the presence of Hp-TGM or TGF-β. Treg induction was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CD25 and CTLA-4. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was evaluated by cellular co-culture suppression assays and cytometric bead arrays for secreted cytokines. Hp-TGM efficiently induced FOXP3 expression (> 60%), in addition to CD25 and CTLA-4, and caused epigenetic modification of the FOXP3 locus to a greater extent than TGF-β. Hp-TGM-induced Tregs had superior suppressive function compared with TGF-β-induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Furthermore, Hp-TGM induced a Treg-like phenotype in in vivo differentiated Th1 and Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. These data indicate Hp-TGM has potential to be used to generate stable human FOXP3+ Tregs to treat IBD and other inflammatory diseases.
| S-EPMC8453874 | biostudies-literature
Project description:Treg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but its use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we target the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-ablated Tregs upregulate cytokine expression, effects on suppressive capacity in vitro manifest slowly and primarily in memory Tregs. Moreover, FOXP3-ablated Tregs retain their characteristic protein, transcriptional, and DNA methylation profile. Instead, FOXP3 maintains DNA methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.
2021-08-03 | GSE176191 | GEO
Project description:Treg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but its use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we target the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-ablated Tregs upregulate cytokine expression, effects on suppressive capacity in vitro manifest slowly and primarily in memory Tregs. Moreover, FOXP3-ablated Tregs retain their characteristic protein, transcriptional, and DNA methylation profile. Instead, FOXP3 maintains DNA methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.
2021-08-03 | GSE164149 | GEO
Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.
2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress
Project description:TIGIT+ Tregs suppress Th1 and Th17 responses while sparing Th2 responses. Analysis of global gene expression of TIGIT+ vs. TIGIT- Tregs from naive mice reveled that TIGIT+ Tregs display an activated phenotype and are enriched for Treg signature genes including the Treg effector molecule Fgl2 which enables them to selectively spare Th2 responses. TIGIT+ and TIGIT- Tregs were sorted from naïve Foxp3-GFP KI mice (pooled spleen and lymph nodes) TIGIT: T cell immunoreceptor with Ig and ITIM domains
2014-12-12 | E-GEOD-56299 | biostudies-arrayexpress
Project description:BATF3-dependent IRF4 binding inhibits FOXP3 in differentiating Tregs
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Project description:Donminant negative transform growth factor receptor II (DNR) mice were served as a murine primary biliary cirrhrosis model. CD4+Foxp3+ Regulatory T cells (Tregs) play a critical role in self-tolerance and in regulating PBC. In order to determine whether DNR mice derived Tregs processed defective function compared with WT Tregs, CD4+Foxp3+ Treg cells were sorted from DNR and WT mice, respectively, then gene expression analysis was performed by using the Affymetrix GeneChip Mouse Genome 430 2.0 arrays CD4+Foxp3+ Tregs were sorted from the spleen of 10-week-old DNR mice and B6 wild-type mice, respectively. RNA of each sample was then extracted and hybridized on Affymetrix microarrays to detail differences between DNR Tregs and WT Tregs in gene expression.
2014-11-05 | E-GEOD-62964 | biostudies-arrayexpress
Project description:Overall, we show that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favor the development of potent suppressor CD4+ and CD8+ FOXP3+ Tregs.
2020-05-27 | GSE151194 | GEO
Project description:Regulatory T cells (Tregs) represent a primary barrier to the development of effective anti-tumor immunity. In the clinic, Tregs are a major contributor to the resistance of immune checkpoint blockade (ICB). Preclinical studies have reported complete tumor regression upon Treg depletion in mice. However, systemic depletion of Tregs is detrimental and sometimes lethal as it causes immune-related adverse effects, such as autoimmune diseases. Here, we report that reprogramming Treg functions, by shifting the expression of FOXP3 from its full-length isoform (FOXP3FL) to a short isoform with exon 2 skipped (FOXP3dE2), promotes the tumor-killing activity of T effectors while limiting the adverse effects of Treg depletion. FOXP3dE2 mRNA expression in triple negative breast cancer tissue positively correlates with overall survival of the patients. Mice expressing only the FOXP3dE2 isoform are resistant to the development of various types of tumors, while the littermate wildtype (WT) mice expressing FOXP3FL isoform exhibit significant tumor growth. Intratumoral injection of FOXP3dE2-directing morpholino (dE2 MO) in WT mice markedly increased IFN-.+ CD4 and CD8 T cells in tumors and consequently inhibited the tumor growth. We developed a novel mouse strain with a humanized Foxp3 exon 2 capable of expressing both FOXP3 isoforms through alternative splicing. This mouse strain showed better antitumor immunity than WT mice and dE2 MO treatment can further enhance their antitumor activity. The antitumor activity of dE2 MO was also confirmed using autologous tumor-infiltrating T cells and patient-derived tumor organoids. Taken together, our results suggest that enhancing FOXP3dE2 isoform expression will reprogram tumor infiltrating Tregs and convert these immune suppressive Tregs to helper-like T cells, thus promoting antitumor immunity.
2025-07-10 | GSE286047 | GEO