In vivo CRISPR screening in autoimmune disease model reveals differential dependence of Th1 and Th17 cells on amino acid transporter SNAT1
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PROVIDER: PRJNA785965 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: The aim of this experiment was to determine the effect of SNAT1 loss on Th1 and Th17 cells. Methods: SNAT1 was knocked out using CRISPR/Cas9 in primary CD4+ T cells polarized to Th1 and Th17 cells in vitro. RNA was then isolated for RNAseq. n=3 biological replicates. Results: SNAT1 mRNA expression was significantly reduced in both Th1 and Th17 cells. Th1 cells displayed consequent changes in the mRNA expression of many other genes (with particular decrease in the expression of glycolysis pathways genes), while Th17 cells had no significant changes in the expression of all other mRNAs detected. Conclusion: This study demonstrates the differential dependence of Th1 and Th17 cells on the amino acid transporter SNAT1.
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Project description:Th17 cells have better stemness and differentiation potential, and under certain circumstances, they can be stimulated to differentiate into other subcelltypes including Th1 and Treg. Here, we report that compared to traditional Th1 and Th17 cells, Th17-derived Th1 cells had greater anti-tumor activity. Both C57 mice ACT therapy and CAR-T therapy models were used to validate it. Mechanism: Th17-derived Th1 cells are able to express Th1 effector molecules as well as retain a lower level of exhaustion than Th1 cells. Additionally, it has a higher amount of type 1 interferon response and a stronger capacity for migration. Our research offers a fresh perspective on how ACT therapy and CAR-T therapy might develop in the future.
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Project description:There is evidence that microglia interact with infiltrating Th1 and Th17 cells and this interaction results in mutual activation. However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to activate microglia is poorly understood. In this study, we tested the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. Interestingly, we found that only Th1-associated factors had the potential to activate microglia while the Th17-associated factors as well as direct contact of Th17 cells with microglia only had a minimal effect. Further Th1-derived factors triggered a proinflammatory M1-type gene expression profile in microglia Microglia harvested from mixed glial cultures were treated with supernatants from Th1- or Th17 cultures. Microglia cultured in medium was used as controls. At 16h post treatment RNA was isolated from the microglia and probed on Agilent´s murine 4x44k microarrays. RNA isolated from four independent experiments were used for the gene expression profiling. Microglia, Th1, Th17
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Project description:This is to compare the gene expression profile of Th1 and Th17 cells. Experiment Overall Design: Two replicates (rep1, rep2) in two groups (Th1, Th17).
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Project description:There is evidence that microglia interact with infiltrating Th1 and Th17 cells and this interaction results in mutual activation. However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to activate microglia is poorly understood. In this study, we tested the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. Interestingly, we found that only Th1-associated factors had the potential to activate microglia while the Th17-associated factors as well as direct contact of Th17 cells with microglia only had a minimal effect. Further Th1-derived factors triggered a proinflammatory M1-type gene expression profile in microglia
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Project description:We aimed to gain a comprehensive understanding of transcriptional profiles of circulating Th1, Th1/17, and Th17 cells in endometriosis patients (n=10) as compared to healthy controls (n=12). Briefly, fresh peripheral blood was collected from subjects, peripheral blood mononuclear cells (PBMCs) were isolated using density centrifugation and then cryopreserved until later bulk analysis. PBMCs were later thawed, CD4+ T cells were magnetically isolated (#17952, StemCell Technologies, Canada) and stimulated with 30ng/mL of PMA and 1ug/mL of Ionomycin and incubated for 4hrs. Cells were then stained for FACS and sorted into viable populations of Th17 (CD3+CD4+IFNg-IL-17+), Th1/17 (CD3+CD4+IFNg+IL-17+), and Th1 (CD3+CD4+IFNg+IL-17-) cells using BD FACSAria™ III. RNA was then isolated from Th1, Th1/17, and Th17 cell populations from patients and controls using a commercially available kit (#74004, Qiagen, Canada). Samples were then quality checked and sent for bulk RNA sequencing (RNAseq) at McGill Genome Centre (MGC, Canada) using Illumina NovaSeq X Plus 10B (Illumina, USA) and subsequent bioinformatic analyses, as per standard pipelines. Briefly, analyses included principal component analysis (PCA), unsupervised and supervised clustering, heatmap generation, differential expression analysis (DEG), volcano plots, fold-change distribution, and Gene Ontology (GO) enrichment analyses. RNA sequencing revealed extensive Th subset reprogramming in endometriosis, most predominately in Th17 cells (2,220 DEGs). Collectively, our findings reveal significant immune remodeling in endometriosis and highlight a distinct, aberrant Th17 cell phenotype, contributing to endometriosis pathophysiology. Ultimately, this work supports the repurposing of IL-23- and IL-17-targeted therapeutics to provide novel options for endometriosis patients, as these therapeutics have been successfully used in other chronic inflammatory diseases and may also target endometriosis-associated comorbidities.
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