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Genome-wide CRISPR screen reveals a key role for integrin avb3 in TH2 cell polarisation [RNA-seq I]

ABSTRACT: T helper 2 (TH2) cells play critical roles in protective immunity against parasitic helminth infections and in tissue repair. However, misdirected TH2 cell responses promote allergy and asthma. Using whole-genome CRISPR-Cas9 screens in developing TH2 cells we defined a functional TH2ome for TH2 differentiation and validated a diverse array of molecules not previously linked to TH2 cell development and function. Strikingly, we discovered that integrin avb3 plays a key and previously unappreciated role in the differential polarisation of TH2 cells and their type 2 cytokine expression. Conversely, we did not identify the LFA-1 integrin which mediates inside-out signalling following TCR ligation as part of the T cell synapse and preferentially promotes TH1 differentiation. We find that TH2 cell expression of integrin avb3 is required for the formation of TH2 cell clusters that exhibit enhanced T cell activation, promoting proliferation and TH2 cell differentiation, and thereby potentiating antigen-driven TH2 cell responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE179207 | GEO | 2022/11/02

REPOSITORIES: GEO

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Genome-wide CRISPR screen reveals a key role for integrin avb3 in TH2 cell polarisation [CRISPRscr]

Project description:T helper 2 (TH2) cells play critical roles in protective immunity against parasitic helminth infections and in tissue repair. However, misdirected TH2 cell responses promote allergy and asthma. Using whole-genome CRISPR-Cas9 screens in developing TH2 cells we defined a functional TH2ome for TH2 differentiation and validated a diverse array of molecules not previously linked to TH2 cell development and function. Strikingly, we discovered that integrin avb3 plays a key and previously unappreciated role in the differential polarisation of TH2 cells and their type 2 cytokine expression. Conversely, we did not identify the LFA-1 integrin which mediates inside-out signalling following TCR ligation as part of the T cell synapse and preferentially promotes TH1 differentiation. We find that TH2 cell expression of integrin avb3 is required for the formation of TH2 cell clusters that exhibit enhanced T cell activation, promoting proliferation and TH2 cell differentiation, and thereby potentiating antigen-driven TH2 cell responses.

2022-11-02 | GSE179206 | GEO

An avb3 integrin checkpoint is critical for efficient TH2 cytokine polarisation and potentiating antigen-specific immunity [RNA-seq]

Project description:To investigate the role of avb3 integrin in TH2 immunity. We performed gene expression profiling analysis using control vs av-KO TH cells.

2022-11-02 | GSE217061 | GEO

An avb3 integrin checkpoint is critical for efficient TH2 cytokine polarisation and potentiating antigen-specific immunity [ChIP-seq]

Project description:To investigate the role of avb3 integrin in TH2 immunity. We performed gene expression profiling analysis using control vs av-KO TH cells.

2022-11-02 | GSE217054 | GEO

Integrin a5, aV, and aVb3 in zebrafish embryos at the 12 somite stage

Project description:Integrins are a major class of heterodimeric adhesion receptors composed of an a and b subunit that mediate cell adhesion to the extracellular matrix (ECM). The extracellular matrix protein fibronectin is important for early vertebrate development, and Integrin a5b1 and aVb3 are the two primary fibronectin receptors. To better define the integrin – ECM protein network at 10-13 somite stage of zebrafish development, we performed co-immunoprecipitation and Mass Spectrometry (MS) based proteomics using FLAG-tagged Integrin a5, aV, and aVb3 expressed in maternal zygotic a5 mutant (MZa5-/-) embryos. We found that Integrin a5b1 and aVb1 are the functional fibronectin receptors, whereas Integrin aVb3 displayed low affinity to both fibronectins (Fn1a and Fn1b). In addition, basement membrane ligands Laminins (lama1, lamb1a, lamc1) are roughly equal in all three datasets while Thrombospondins (thbs3b, thbs4b) and cartilage oligomeric matrix protein (comp/thbs5) are found exclusively in the aV dataset. Our results suggest a diverse role of aV class integrins in ECM protein recruitment.

2021-09-10 | PXD024665 | Pride

The Effects of avb3 Integrin Signaling on the Transcriptome of an Immortalized Line of Human Trabecular Meshwork Cells (TM-1)

Project description:Purpose: To study the effects of overexpressing either a wild type (WT) or a constitutively active (CA) avb3 integrin on the transcriptome of an immortalied line of human trabecular meshwork cells. Methods: RNA was collected from four samples each of control cells expressing an empty vector (EV), cells overexpressing a WT avb3 integrin (WTb3) or a CA avb3 (CAb3) integrin. All cells had been cultured at confluence for 24 hr in 1%FBS-containing medium. RNA libraries were prepared using 1µg of RNA/sample with the TruSeq RNA sample preparation kit and sequenced on four lanes of an Illumina HiSeq 2500 System. Quality control was performed on the sequencing reads using fastq and skewer trimming software was used to preprocess raw fastq files. A quality control pipeline was then applied and each RNA-Seq sample was subsequently normalized by the method of trimmed mean M-values prior to DGE analysis using EdgeR. Results: 5,186 genes had significantly altered expression (p<0.05) in WTb3 cells compared to EV cells (2,645 upregulated vs 2541 downregulated); 8,249 genes had significantly altered expression (p<0.05) in CAb3 cells compared to EV cells (4,094 upregulated vs 4,255 downregulated). However, 6,999 genes had significantly altered expression (p<0.05) in WTb3 cells vs CAb3 cells (3,524 upregulated vs 3,475 downregulated). Conclusions: Overexpressing of both a WT avb3 and a constitutively active avb3 integrin caused signficant alterations in the transcriptome of immortalized TM-1 cells, however constitutive activation of avb3 signaling had a more pronounced effect on the TM-1 transcriptome than did mere overexpression of the integrin.

2021-08-24 | GSE180407 | GEO

Analysis of human myeloma cell lines expressing beta 3 integrin

Project description:The aim of these experiments was designed to compare gene expression in human myeloma cell lines expressing beta 3 integrin vs counterpart cell lines that do not express beta 3 integrin. Keywords: Gene expression,cell lines, siRNA Phenotype characterization of both primary and cultured myeloma plasma cells was assessed by flow cytometry (FACScanto, Becton Dickinson, San Jose, CA) using a panel of MoAbs or antisera to the following markers: CD138, CD38, CD56, k/l chains, CD20, CD44, CD54, alphav and beta3 chains. The microarray analysis was performed on: myeloma bone resorbing cell lines alphav-beta3 positive and the same cell line silenced for the integrins; myeloma non bone resorbing cell lines negative for the expression of avb3.

2010-05-19 | E-GEOD-15867 | biostudies-arrayexpress

A proteomics approach to isolating neuropilin-dependent α5 integrin trafficking pathways: neuropilin 1 and 2 co-traffic α5 integrin through endosomal p120RasGAP to promote polarised fibronectin fibrillogenesis in endothelial cells

Project description:Integrin trafficking to and from membrane adhesions is a crucial mechanism that dictates many aspects of a cell’s behaviour, including motility, polarisation, and invasion. In endothelial cells (ECs), the intracellular traffic of α5-integrin is regulated by both neuropilin 1 (NRP1) and neuropilin 2 (NRP2), yet the redundancies in function between these co-receptors remain unclear. Moreover, the endocytic complexes that participate in NRP-directed-traffic remain poorly annotated. Here we identify an important role for the GTPase-activating protein p120RasGAP in ECs, promoting the recycling of α5-integrin from early endosomes. Mechanistically, p120RasGAP enables transit of endocytosed α5-integrin-NRP1-NRP2 complexes to Rab11+ recycling endosomes, promoting cell polarisation and fibronectin (FN) fibrillogenesis. Silencing of both NRP receptors, or p120RasGAP, resulted in the accumulation of α5-integrin in early endosomes, a loss of α5-integrin from surface adhesions, and attenuated EC polarisation. Endothelial-specific deletion of both NRP1 and NRP2 in the postnatal retina recapitulated our in vitro findings, severely impairing FN fibrillogenesis and polarised sprouting. Our data assign an essential role for p120RasGAP during integrin traffic in ECs and support a hypothesis that NRP receptors co-traffic internalised cargoes. Importantly, we utilise comparative proteomics analyses to, for the first time, isolate a comprehensive map of NRP1-dependent and NRP2-dependent-α5-integrin interactions in ECs.

2024-05-20 | PXD051778 | Pride

The Effects of avb3 Integrin Signaling on the Transcriptome of an Immortalized Line of Human Trabecular Meshwork Cells (TM-1)

Project description:The Effects of avb3 Integrin Signaling on the Transcriptome of an Immortalized Line of Human Trabecular Meshwork Cells (TM-1)

| PRJNA748071 | ENA

DNA methylation profiling of human CD4+T-cells in-vitro polarized towards Th1 and Th2 time-series

Project description:Differentiation of CD4+T-cells into effector subsets is a critical component of the adaptive immune system and an incorrect response can lead to autoimmunity or immune deficiency. Cellular differentiation including T-cell differentiation is accompanied by large-scale epigenetic remodeling, including changes in DNA methylation at key regulators of T-cell differentiation. The TET family of enzymes were recently shown to be able to catalyse methylated cytosine (5mC) into 5-hydroxymethylcytosine (5hmC) enabling a pathway of active removal of DNA methylation. Here, we characterize 5hmC, 5mC and transcriptional dynamics during human CD4+T-cell polarisation in a time series approach and relate these changes to profiles in ex-vivo CD4+memory subsets. We observed large-scale remodelling during early CD4+T-cell differentiation which was predictive of subsequent changes during late time points, these changes were also related to disease associated regions which we show can act as functional regulatory elements. This dataset was designed to assess how gene expression changes over time during human CD4+T-cell polarization towards Th1 and Th2. DNA methylation was assessed in relationship to 5hmC levels and changes (see data series), we observed that regions gaining 5hmC early was highly predictive of regions losing DNA methylation during late time points. This submission contains data from the DNA methylation by array profiling of human CD4+T-cells in-vitro polarized towards Th1 and Th2 time-series. It is part of series containing 5hmC and DNA methylation profiling of the same samples. See related experiments E-MTAB-4685, E-MTAB-4686, E-MTAB-4687, E-MTAB-4689.

2016-07-11 | E-MTAB-4688 | biostudies-arrayexpress

Potent anti-tumor immunity and reversal of CD8 T cell exhaustion by spatially and functionally targeting Treg cells in the tumor microenvironment

Project description:Regulatory T cells (Tregs) are a key mediator of resistance to cancer immunotherapy, including anti-PD-(L)1 immune checkpoint blockade (ICB). Tregs perpetually infiltrate tumors and hamper effective anti-tumor immunity. The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on CD8+ T cell exhaustion remains elusive. Herein, we report that heat shock protein gp96 (GRP94) is indispensable for Treg infiltration into the tumor, primarily through gp96’s roles in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 (αL integrin) but not integrin αV, CD103 (αE) or β7 was required for Treg homing into the tumors. Loss of Treg infiltration into the TME by genetically deleting gp96/LFA-1 potently induces rejection of multiple ICB-resistant murine cancer models in a CD8+ T cell dependent manner without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/phosphorylated STAT5 (pSTAT5) signaling pathway, which also contributes to tumor regression. Notably, by a mechanism in part through competing for IL-2 in the TME, intra-tumoral Tregs prevent activation of CD8+ tumor-infiltrating lymphocytes (TILs), drive TOX induction and induce bona fide CD8+ T cell exhaustion. By contrast, Treg ablation leads to a striking CD8+ T cell activation without TOX induction, demonstrating clear uncoupling of the two processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and intratumoral CD8+ T cell exhaustion. We suggest that, Treg-specific targeting of gp96/LFA-1 represents a novel strategy for cancer immunotherapy without inflicting autoinflammatory conditions.

2024-05-05 | GSE266362 | GEO

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