Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Interferon-γ Converts Human Microvascular Pericytes into Negative Regulators of Alloimmunity through Induction of Indoleamine 2,3-Dioxygenase 1

ABSTRACT: Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft post-capillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces -PC-mediated immunoregulatory effects. Adoptively transferred T cells induced PC expression of IDO1 in allogeneic human skin grafts on immunodeficient mice. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109322 | GEO | 2018/05/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Tryptophan depletion provokes the production and presentation of in-frame tryptophan to phenylalanine substitutions

Project description:Activated T cells secrete interferon-gamma (IFN) that triggers an intra-cellular tryptophan shortage through the activation of the Indoleamine 2,3-Dioxygenase 1 (IDO1) enzyme. Surprisingly, we here show that despite tryptophan depletion, in-frame protein synthesis bypassing tryptophan codons continues. Using mass spectrometry, we identified tryptophan to phenylalanine (W>F) substitution as the major event that facilitates in-frame protein synthesis in IFN-treated and tryptophan-depleted cells. We validated their expression using in vitro reporter assays, and pinpoint tryptophanyl-tRNA synthetase (WARS1) as the candidate gene that accounts for this event. We named these mRNA-translation-driven aberrations ‘substitutants’ to distinguish them from somatic genetic variants. To uncover their biological relevance, we interrogated cancer proteomes and phosphoproteomes of breast, lung and kidney cancers. Interestingly, we specifically identified a high level of tryptic peptides containing W>F substitutants with strong association to IDO1 expression, T cell activity, p53 mutations, and oncogenic MAPK signaling, indicating a role of infiltrating T cells in their production and highlighting cancer relevance. We further show that substitutants can impair protein function and be processed and presented at the cell surface to elicit immune cell recognition. Indeed, immunopeptidomics data from of colorectal-cancer organoids and glioblastoma cell lines revealed a large number of W>F substitutant-peptides being presented on HLA class I molecules following IFN treatment. Thus, W>F substitutants are a novel form of non-genetic mutations induced by tumor-infiltrating T cells with potential impact on gene function and on the repertoire of neopeptides presented by cancer cells.

2021-12-23 | PXD028921 | Pride

Anti-tumor immunity induces the presentation of aberrant peptides in melanoma

Project description:Extensive tumor inflammation, reflected by high levels of infiltrating T-cells and Interferon gamma (IFNγ) signaling, is thought to improve checkpoint immunotherapy response. However, many tumors escape by activating multiple cellular pathways that induce immunosuppression. One pivotal immune-suppressive mechanism is the production of Tryptophan metabolites along the kynurenine pathway by IFNγ-induced IDO1 enzyme production. However, phase III clinical trials using chemical inhibition of IDO1 in combination with PD1 pathway blockade failed to improve melanoma treatment, suggesting incomplete understanding of the role of IDO1 and the consequent Tryptophan degradation on mRNA translation and cancer progression. Here, we investigated the effects of prolonged IFNγ treatment on mRNA translation in melanoma cells by ribosome profiling. Our results suggest that IFNγ-induced IDO1-mediated Tryptophan depletion may play a key role in the immune recognition of melanoma cells, by inducing the production and presentation of aberrant peptides.

2020-10-18 | GSE142822 | GEO

Transcriptomic profiles of splenic Gr-1+ cells from IDO-KO hosts and WT hosts after bone marrow transplantation

Project description:Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has also immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) alloBMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and IL-10, Ido1-/- Gr1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immunesuppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities, and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by Nacetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a novel mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

2021-12-20 | GSE163730 | GEO

Gene expression profile at single cell level of alloantigen-specific TEa CD4+ T cells after heart transplantation

Project description:Alloreactive CD4+ T cells play a central role in allograft rejection, We used single cell RNA sequencing (scRNA-seq) to analyze the cell states of alloreactive CD4+ T cells in periphery and allografts to better understand how alloreactive CD4+ T cells drive allograft rejection.

2023-09-28 | GSE221337 | GEO

Kronik2008 - Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics

Project description:This mathematical model describes interactions between glioma tumors and the immune system that may occur following direct intra-tumoral administration of ex-vivo activated alloreactive cytotoxic-T-lymphocytes (aCTLs) as part of adoptive immunotherapy. The model includes descriptions of aCTL, neoplastic cells, MHC class I and II molecules, TGF-beta and IFN-gamma.

2024-09-02 | BIOMD0000000808 | BioModels

Activating CD8 T cell clones via the T cell receptor complex in the absence and presence of cyclosporine A

Project description:Comparison of a cyclosporine-resistant murine CD8 T cell clone to a cyclosporine-sensitive murine T cell clone during activation (CSA = Cyclosporine A) Chronic allograft rejection is the leading cause of morbidity/mortality in solid organ and bone marrow transplant patients. It occurs in the setting of potent calcineurin and mTOR inhibitor therapies, implying that T cells mediating chronic rejection can function with compromised calcineurin-NFAT or IL-2 receptor signaling pathways. In murine models the T cells mediating allograft rejection in the setting of calcineurin inhibitor therapy are CD8 T cells making IFN-gamma without a requirement for perforin. It is not known whether these pathologic T cells are a unique subset or how they function. In parallel other animal model research has shown that alloepthelial cells residing in the donor organ are critical targets for rejection. While investigating T cell-alloepithelial cell interactions, we discovered an unusual alloreactive CD8 T cell population that recognized MHC class II I-Abm12. A CD8 T cell clone derived from that population was intrinsically-resistant to cyclosporine and rapamycin without prior exposure to either in vivo or in vitro. Microarray analysis comparing the novel CD8 T cell clone to a conventional CD8 CTL clone specific for MHC class I Kbm1 suggested that the TCR signaling pathway responsible for cyclosporine-resistance utilized the Aryl Hydrocarbon Receptor (AHR). Two T cell clones x 2 experimental conditions x 4 replicates

2014-04-14 | E-GEOD-46122 | biostudies-arrayexpress

The self-peptide repertoire plays a critical role in transplant tolerance induction

Project description:While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC I constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify almost 40% of alloreactive T cells within a polyclonal population. To our knowledge, this represents the first example of such an approach in the context of direct allorecognition.

2021-12-06 | PXD023015 | Pride

The self-peptide repertoire plays a critical role in transplant tolerance induction

2021-12-06 | PXD022695 | Pride

Murine Model of Familial Hemophagocytic Lymphohistiocytosis Hepatitis is Mediated by IFN-γ in a Predominantly Hepatic-Intrinsic Manner

Project description:Interferon gamma (IFN-γ) is the main cytokine driving Familial Hemophagocytic Lymphohistiocytosis (FHL) organ dysfunction. Hepatocytes are known to have IFN-γ receptor (IFN-γ-R). Blockade of IFN-γ pathway ameliorates FHL hepatitis, in animal models and in humans. However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. We report that IFN-γ-mediated hepatic injury in the murine model of FHL is caused by direct effect on the liver and has a necessary role in recruitment of the inflammatory mediators of injury in FHL: inflammatory monocytes and CD8+ effector memory T lymphocytes (CD8+ CD44hi CD62Llo) (Tem).

2022-06-02 | GSE168086 | GEO

Dysfunction of S100A4+ effector memory CD8+ T cells aggravates asthma

Project description:Progressive loss of effector functions, especially IFN-γ secreting capability, in effector memory CD8+ T (CD8+ TEM) cells plays a causal role in asthma worsening. However, the mechanisms of CD8+ TEM cell dysfunction remain elusive. Here, we report that S100A4 drives CD8+ TEM cell dysfunction, impairing their protective memory response and promoting asthma worsening in OVA-induced asthma model. We find that allergic CD8+ TEM cells contain two subsets based on S100A4 expression. S100A4+ subsets exhibit dysfunctional effector phenotypes with increased proliferative capability, whereas S100A4- subsets retain effector function but are more inclined to apoptosis, giving rise a dysfunctional CD8+ TEM cell pool. Mechanistically, S100A4 upregulation of mitochondrial metabolism results in a decrease of acetyl-CoA levels, which impair the transcription of effector genes, especially ifn-γ, facilitating cell survival, tolerance and memory potential. Our findings thus reveal general insights into how S100A4 reprograms CD8+ TEM cells into dysfunctional and less protective phenotypes to promote asthma worsening.

2022-03-11 | GSE162116 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data