Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Engineered IL-10 variants elicit potent immuno-modulatory activities at therapeutic low ligand doses

ABSTRACT: Interleukin-10 is a dimeric cytokine with potent anti-inflammatory and anti-cancer activities. Despite its immune-regulatory potential, IL-10-based therapies have shown only marginal benefits in the clinic. Here we have explored whether the stability of the IL-10-receptor complex contributes to IL-10 immuno-modulatory potency. For that, we have generated an IL-10 mutant with greatly enhanced affinity for its IL-10Rβ receptor via yeast surface display. The affinity enhanced IL-10 variants formed surface active complexes more efficiently than the wild-type cytokine and triggered more potent STAT1 and STAT3 activation in human monocytes and CD8 T cells. This in turn led to more robust induction of IL-10-mediated gene expression programs at a wide range of ligand concentrations in both human cell subsets. IL-10 regulated genes involved in monocyte energy homeostasis, migration and trafficking, and genes involved in CD8 T cell exhaustion. Interestingly, at non-saturating doses, IL-10 lost key components of its gene-expression program, which may explain its lack of efficacy in a clinical set up. Remarkably, our engineered IL-10 variant exhibited a more robust bioactivity profile than IL-10 wt at all the doses tested in monocytes and CD8 T cells. Our study provides unique insights into how IL-10-receptor complex stability contributes to fine-tune IL-10 biology, and open new opportunities to revitalize failed IL-10 therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146438 | GEO | 2020/09/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IL-6R identifies early differentiated human effector memory CD8+ T cells that potently expand and produce IL-2 and IL-13

Project description:We found a unique subset of effector memory (EM) CD8+ T cells that expressed high levels of IL-6 receptor in human peripheral blood. These cells which also expressed high levels of IL-7Ra (referred to as IL-6R high IL-7Rahigh cells) had the a distinct gene expression profile and cellular characteristics compared to other EM CD8+ T cells. IL-6R high IL-7Ra high cells were early differentiated EM CD8+ T cells with decreased expression of T-bet, KLRG1, perforin and granzyme B. These cells had increased cell proliferation likely secondary to enhanced IL-2 production and high affinity IL-2R expression. IL-6R high IL-7Ra high EM CD8+ T cells exclusively produced high levels of IL-2, IL-5, IL-9 and IL-13 although IFN-r was produced by this cell subset and other EM CD8+ T cells. Of interest, IL-6R high IL-7Ra high EM CD8+ T cells expanded in the peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and asthma where CD8+ T cells, IL-13 and IFN-r are suggested to be involved in the pathogenesis. Being the early-differentiated EM CD8+ T cells with a potent capacity to proliferate, survive and generate multiple cytokines, IL-6R high IL-7Ra high EM CD8+ T cells may serve as a primary reservoir for effector CD8+ T cells which potently expand and produce cytokines upon immune stimulation. Duplicate experiments were performed for each condition. In each condition, we independently prepared total RNA using the RNeasy mini kit (Qiagen) and assessed RNA integrity using Bioanalyzer 2100 (Agilent)- RINs were close to 10 for all samples. RNA was then amplified and hybridized to the Illumina HumanHT-12 v4.0 BeadChip, according to Illumina standard protocols.

2012-12-31 | E-GEOD-34562 | biostudies-arrayexpress

Metabolic Reprogramming of Terminally Exhausted CD8+ T-cells by Interleukin-10 Enhances Anti-Tumour Immunity

Project description:Terminally exhausted CD8+ T-cells, which hold certain level of anti-tumour cytotoxicity but largely reduced proliferation capacity, contribute directly to tumour growth control. However, this subpopulation do not respond to immune checkpoint blockades or most existing immunotherapies and are difficult to be reactivated. Here, we show that a half-life extended interleukin (IL)-10/Fc fusion protein directly expands the terminally exhausted CD8+ TILs and sustains their effector functions through in vivo metabolic reprogramming, leading to eradication of established solid tumours and durable cures in a majority of treated mice when combined with adoptive T-cell transfer immunotherapy. Our results provide preclinical evidence that IL-10/Fc is a safe and highly effective therapy that acts on a specific subset of CD8+ TILs distinct from those responding to immune checkpoint blockades. Thus, IL-10/Fc could complement and synergize with existing cancer immunotherapies for enhanced efficacy and response rates. We find that IL-10/Fc reprograms T-cell metabolism by promoting oxidative phosphorylation through the mitochondrial pyruvate carrier, suggesting that metabolic reprogramming is sufficient to revitalize terminally exhausted CD8+ TILs.

2021-04-01 | GSE168990 | GEO

Transcription profiling of mouse CD8 T cells reveals prolonged IL-2R alpha expression on virus-specific CD8+ T cells favors terminal effector differentiation in vivo

Project description:CD25, the high affinity interleukin-2 (IL-2) receptor alpha-chain, is rapidly upregulated by antigen-specific CD8+ T cells after T cell receptor stimulation. We demonstrated that during an acute viral infection, CD25 expression was dynamic, and a subset of virus-specific CD8+ T cells sustained CD25 expression longer than the rest. Examination of the in vivo fate of effector CD8+ T cells exhibiting differential responsiveness to IL-2 revealed that CD25lo cells, which were relatively less sensitive to IL-2, preferentially upregulated CD127 and CD62L and gave rise to the functional long-lived memory pool. In contrast, CD25hi cells that accumulate enhanced IL-2 signals, proliferated more rapidly, were prone to apoptosis, exhibited a more pronounced effector phenotype, and appeared to be terminally differentiated. Sustained IL-2 receptor signaling resulted in increased CD8+ T cell proliferation, higher granzyme B expression and exaggerated contraction after antigen clearance. These data support the hypothesis that prolonged IL-2 signals during priming promote terminal effector differentiation of CD8+ T cells. Experiment Overall Design: An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study we have performed genomic profiling of terminal effectors and memory precursors as defined by CD25 heterogeneity, towards better understanding the generation of these subsets. The two effector subsets were FACS purified based on the amount of cell surface CD25 expression into CD25lo and CD25hi subsets during the early expansion phase (Days 3-4 post-infection) and analyzed for their gene expression profiles (by genome-wide microarray analyses).

2010-02-17 | E-GEOD-19825 | biostudies-arrayexpress

Prolonged IL-2R alpha expression on virus-specific CD8+ T cells favors terminal effector differentiation in vivo

2010-01-21 | GSE19825 | GEO

IL-34 actions on FOXP3+ Tregs and CD14+ monocytes control human graft rejection

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

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein (scRNA-Seq)

Project description:Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation and anti-tumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Ra with higher affinity, triggers STAT5 activation and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Finally, we find that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.

2022-12-02 | GSE213440 | GEO

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein (RNA-Seq)

2022-12-02 | GSE213439 | GEO

Exogenous Interleukin-10 versus Glucocorticoids: Effect on Gene Expression and Pro-inflammatory Cytokine Release in Polymorphonuclear Leukocytes and Monocytes of the Newborn

Project description:INTRODUCTION: Persistent lung inflammation, with an influx of polymorphonuclear leukocytes and monocytes, occurs early in bronchopulmonary dysplasia. We hypothesized that: 1) that interleukin-10, a potent anti-inflammatory cytokine, would cause a markedly different gene expression profile compared to dexamethasone in these cells, and 2) monocyte insensitivity to dexamethasone was related to glucocorticoid receptor expression. RESULTS: For polymorphonuclear leukocytes, there were <20% of genes changing expression in common between interleukin-10 and dexamethasone. The monocyte had 5 times the number of genes changing expression with interleukin-10 compared to the polymorphonuclear leukocyte. Dexamethasone, in the therapeutic range, had no effect on gene expression in monocytes. The order of potency for inhibition of interleukin-8 release from monocytes was IL-10>betamethasone>> dexamethasone and hydrocortisone. Glucocorticoid potency was directly related to the degree of glucocorticoid receptor translocation to the monocyte nucleus. DISCUSSION: Gene expression profiles by IL-10 versus dexamethasone indicates that there may be major differences in efficacy and adverse effects if interleukin-10 is used for therapy in the future. Betamethasone may be a better therapeutic choice than dexamethasone. METHODS: Isolated cord blood cells were pre-incubated with anti-inflammatory agents prior to endotoxin stimulation. Measurements were made by microarrays, RT-qPCR, ELISA, and Western blots. Isolation of cord blood polymorphonuclear leukocytes and monocytes separately from 5 subjects. Endotoxin stimulation in cell culture for 4 hours. Comparison of gene expression between endotoxin alone versus endotoxin-stimualted cells pretreated with interleukin-10 or dexamethasone (at equimolar, therapeutic levels, 10-8 M. Cell Types : MONOs, PMNs; Treatments: LPS, LPS+IL-10, LPS+DEX

2012-02-16 | E-GEOD-35683 | biostudies-arrayexpress

Engineered IL-10 variants elicit potent immuno-modulatory activities at therapeutic low ligand doses

Project description:Engineered IL-10 variants elicit potent immuno-modulatory activities at therapeutic low ligand doses

| PRJNA610578 | ENA

Expression data from IL-10+ and IL-10- CD8 T cells

Project description:IL-10 is an anti-inflammatory cytokine that has been shown to be produced by antigen-specific CD8 T cells at the peak of viral encephalitis. We found that IL-10+CD8 T cells are more activated and cytolytic than IL-10-CD8 T cells. We used microarrays to detect gene expression changes in directly ex vivo sorted CNS IL-10+ and IL-10- CD8 T cells from a neurotropic J2.2-V-1-infected mouse.

2010-12-07 | GSE25846 | 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