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Progenitor-Derived Human Endothelial Cells Evade Alloimmunity by CRISPR/Cas9-Mediated Complete Ablation of MHC Expression

ABSTRACT: Progenitor-Derived Human Endothelial Cells Evade Alloimmunity by CRISPR/Cas9-Mediated Complete Ablation of MHC Expression

PROVIDER: PRJNA540268 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8985430_1.fastq.gz	Fastqsanger.gz
	SRR8985430_2.fastq.gz	Fastqsanger.gz
	SRR8985440_1.fastq.gz	Fastqsanger.gz
	SRR8985440_2.fastq.gz	Fastqsanger.gz
	SRR8985450_1.fastq.gz	Fastqsanger.gz

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Progenitor-Derived Human Endothelial Cells Evade Alloimmunity by CRISPR/Cas9-Mediated Complete Ablation of MHC Expression

Project description:Purpose: To compare human progenitor cell-derived endothelial cells ablated of MHC molecules to endothelial cells transduced with control vector after IFN-y treatment

2019-11-12 | GSE130443 | GEO

Progenitor-derived human endothelial cells evade alloimmunity by CRISPR/Cas9-mediated complete ablation of MHC expression.

Project description:Tissue engineering may address organ shortages currently limiting clinical transplantation. Off-the-shelf engineered vascularized organs will likely use allogeneic endothelial cells (ECs) to construct microvessels required for graft perfusion. Vasculogenic ECs can be differentiated from committed progenitors (human endothelial colony-forming cells or HECFCs) without risk of mutation or teratoma formation associated with reprogrammed stem cells. Like other ECs, these cells can express both class I and class II major histocompatibility complex (MHC) molecules, bind donor-specific antibody (DSA), activate alloreactive T effector memory cells, and initiate rejection in the absence of donor leukocytes. CRISPR/Cas9-mediated dual ablation of β2-microglobulin and class II transactivator (CIITA) in HECFC-derived ECs eliminates both class I and II MHC expression while retaining EC functions and vasculogenic potential. Importantly, dually ablated ECs no longer bind human DSA or activate allogeneic CD4+ effector memory T cells and are resistant to killing by CD8+ alloreactive cytotoxic T lymphocytes in vitro and in vivo. Despite absent class I MHC molecules, these ECs do not activate or elicit cytotoxic activity from allogeneic natural killer cells. These data suggest that HECFC-derived ECs lacking MHC molecule expression can be utilized for engineering vascularized grafts that evade allorejection.

| S-EPMC6824302 | biostudies-literature

Complete Haplotype Phasing of the MHC and KIR Loci with Targeted HaploSeq

Project description:Rapid advances in biochemical technologies have enabled several strategies for typing candidate HLA alleles, but linking them into a single MHC haplotype structure remains challenging. Here we have developed a multi-loci haplotype phasing technique and demonstrate its utility towards phasing of MHC and KIR loci in human samples. We accurately (~99%) reconstruct the complete haplotypes for over 90% of sequence variants spanning the 4-megabase region of these two loci. By haplotyping a majority of coding and non-coding alleles at the MHC and KIR loci in a single assay, this method has the potential to assist transplantation matching and facilitate investigation of the genetic basis of human immunity and disease. Complete haplotype phasing of 2 loci (MHC and KIR) in 1 human cell line.

2016-02-01 | E-GEOD-65726 | biostudies-arrayexpress

Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas [DLBCL_GSK126]

Project description:Tumors frequently subvert MHC class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well-defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.

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Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas [DLBCL_RNAseq]

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Eosinophils Restrain Humoral Alloimmunity after Lung Transplantation

Project description:Eosinophils Restrain Humoral Alloimmunity after Lung Transplantation

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Complete Haplotype Phasing of the MHC and KIR Loci with Targeted HaploSeq

2016-02-01 | GSE65726 | GEO

Eosinophils Restrain Humoral Alloimmunity after Lung Transplantation [scRNA-seq]

Project description:While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils’ role in alloimmunity based on context and organ type. Due to their prevalence in the lung, and their defined role in other pulmonary pathology such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody secreting cell differentiation and resulted in de novo-generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD1+ T follicular helper cells (Tfh) which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naïve CD4+ T cells. Our data thus describe a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggests that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.

2025-01-14 | GSE223268 | GEO

Dietary suppression of MHC-II expression in intestinal epithelial cells enhances intestinal tumorigenesis

Project description:Little is known about how interactions between diet, intestinal stem cells (ISCs) and immune cells impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in intestinal epithelial cells including ISCs. This decline in epithelial MHC-II expression in a HFD correlates with reduced diversity of the intestinal microbiome and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor (PRR) and IFN g signaling regulate epithelial MHC-II expression where genetic ablation of these signaling pathways dampen MHC-II epithelial expression. Interestingly, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts when transplanted into immune-component hosts but not immune-deficient hosts, thus implicating a role for epithelial MHC-II-mediated immune surveillance in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD perturbs a microbiome – stem cell – immune cell crosstalk in the intestine and contributes to tumor initiation through the dampening of MHC-II expression in pre-malignant ISCs.

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B4GALT5 and B3GNT3 downregulate MHC-I levels on tumor cells, thereby suppressing CD8+ T cell responses in pancreatic ductal adenocarcinoma.

Project description:Immune evasion is a critical event in the progression of pancreatic ductal adenocarcinoma (PDAC), where the expression of MHC-I molecules is frequently suppressed in the majority of PDAC cells, serving as a strategy for tumor cells to evade immune surveillance. Reduced MHC-I expression allows tumor cells to escape recognition and killing by CD8+ T cells, thereby promoting their growth and dissemination within the body. In this study, we identified a significant negative correlation between the expression of B3GNT3 and B4GALT5 and the levels of MHC-I on tumor cells.

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