Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthetic expansion of brain regulatory T cells effectively prevents neuroinflammatory disease II

ABSTRACT: An adaptive immunological component to neuroinflammatory diseases is increasingly being recognized. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain allows for the potential therapeutic exploitation. As the most potent known anti-inflammatory mediators, Tregs have the capacity to reduce inflammation and promote tissue repair, with a key limitation being the small number present in brain tissue. Here we demonstrate that transgenic ‘micro-dosing’ of IL-2 production to the brain allows the efficient expansion of the brain-resident Treg population. This approach, using expression of IL-2 within the normal physiological range but redirected to the brain, allows a 10-fold accumulation of Treg numbers within the brain without any increase in the Treg numbers in circulating or peripheral tissues. No alteration was observed in the frequency or transcriptional profile of non-Treg populations within the brain, and, apart from the numerical expansion, brain-resident Tregs were unaltered in their transcriptional profile. Mice with expanded brain-resident Treg numbers were protected from neuroinflammation and damage in mouse models of traumatic brain injury, stroke and Multiple Sclerosis, with substantial reductions in inflammation and histological damage, and improvements in clinical measurements. To produce a treatment with translational potential, we engineered a viral vector delivery system, capable of specific production of IL-2 in the brain. This treatment approach provided a titratable expansion of brain Tregs, and effective protection against neuroinflammatory disease, with potential translation to the patient context.

ORGANISM(S): Mus musculus

PROVIDER: GSE156935 | GEO | 2022/06/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

RNAseq analysis for tails, and ears from Ikbkb mut/mut and Ikbkb wt/wt mice

Project description:Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. We report that mice heterozygous for an Ikbkb gain-of-function (GoF) mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3+ CD25+ Tregs of which a subset express IL-17. These modified Tregs were enriched at the inflamed tissues and spleen, and their transfer was sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs revealed expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-kB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.

2024-01-09 | GSE248917 | GEO

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.

2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

Project description:The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune-modulation and a delivery system capable of crossing the blood-brain-barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

2022-03-21 | GSE153427 | GEO

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

2022-03-21 | GSE179176 | GEO

Essential and non-overlapping IL-2Rα-dependent signaling for thymic development and peripheral homeostasis of regulatory T cells

Project description:IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution for IL-2 during Treg thymic development, peripheral homeostasis, and lineage stability remains unclear. Here we show that IL-2R signaling is essential for thymic Tregs at an early step for expansion/survival and a later step for functional maturation. Using selective deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling was absolutely essential for their persistence whereas Treg lineage stability was IL-2-independent. CD25 knockout peripheral Tregs showed increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2 transcriptional signature was noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, where peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.

2019-02-01 | GSE121883 | GEO

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

2015-11-01 | GSE63455 | GEO

Gene expression by Treg subsets

Project description:Thymic-derived natural T regulatory cells (nTregs) are characterized by functional and phenotypic heterogeneity. Recently, a small fraction of peripheral Tregs have been shown to express Klrg1, but it remains unclear the extent Klrg1 defines a unique Treg subset. Here we show that Klrg1+ Tregs represent a terminally differentiated Treg subset derived from Klrg1- Tregs. This subset is a recent antigen-responsive and a highly activated short-lived Treg population that expresses enhanced levels of Treg suppressive molecules and that preferentially resides within mucosal tissues. The development of Klrg1+ Tregs also requires extensive IL-2R signaling. This activity represents a distinct function for IL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and other properties are analogous to terminally differentiated short-lived CD8+ T effector cells. Our findings suggest that an important pathway driving antigen-activated conventional T lymphocytes also operates for Tregs. Gene expression analysis was performed of this and other Treg subsets based on expression of CD62L, CD69, and Klrg1 to define the molecular properties of Klrg1+ Tregs and its relationship to other Treg subsets found in the peripheral immune tissues. Mice were euthanized, spleen cell preparations were made, and each Treg subset was isolated by FACS cell sorting. RNA was immediately prepared for processing.

2012-08-06 | E-GEOD-36527 | biostudies-arrayexpress

Transcriptional profiling of Regulatory T-cells isolated from adult skin and skin draining lymph nodes (SDLNs)

Project description:Purpose: The goals of this study were to identify preferential gene expression signatures that are unique to telogen skin resident Tregs relative to peripheral Tregs Methods: Tregs from telogen skin and SDLNs were purified by cell sorting (using the Treg GFP reporter mouse line Foxp3-DTR/GFP) to generate mRNA transcription profiles. Results: Transcriptional profiling revealed a unique Skin treg signature relative to SDLN Tregs Conclusion: Our study represents the first detailed analysis of the skin Treg transcriptome. mRNA profiles of skin and SDLN Tregs isolated from 6 week old Foxp3-DTR/GFP mice.

2017-04-28 | E-GEOD-76138 | biostudies-arrayexpress

Single-cell RNA sequencing of IkbkbV203I Tregs from spleen and bone marrow

Project description:Foxp3+ regulatory T cells (Tregs) typically suppress immune responses to prevent autoimmunity and aberrant inflammatory responses. In addition, tissue resident Tregs contribute to homeostasis and repair of non-lymphoid parenchyma. We generated a mouse model of a human inborn error of immunity arising from a gain-of-function missense mutation inIkbkband observed cell-intrinsic expansion of Tregs that maintained expression of Foxp3 and CD25. Remarkably, a subset of Tregs in this model expressed IL-17. We show by scRNA seq that NF-kB regulates specifically the expansion of a subset tissue Tregs, previously names skin NLT. Mice homozygous for theIkbkbmutation developed psoriasis, while homozygous mice also developed features of psoriatic arthritis. Skin NLTs were enriched at sites of pathology, and disease was dependent on the presence of pathological Tregs. Thus, we identify canonical NF-kB as a regulator tissue Treg differentiation and that this pathway can explain aberrant tissue healing responses that underpin psoriasis and psoriatic arthritis.

2024-01-09 | GSE228385 | GEO

RNA-seq of expanded human CRISPR/HDR-mediated FOXP3-KO naive Tregs, Cas9 naive Tregs, and conventional T cells

Project description:Treg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but its use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we target the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-ablated Tregs upregulate cytokine expression, effects on suppressive capacity in vitro manifest slowly and primarily in memory Tregs. Moreover, FOXP3-ablated Tregs retain their characteristic protein, transcriptional, and DNA methylation profile. Instead, FOXP3 maintains DNA methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.

2021-08-03 | GSE176191 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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