Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Receptor-tethered orthogonal IL-2 enhances regulatory T cell therapy

ABSTRACT: Regulatory T cell (Treg) therapy is an emerging platform for controlling immune overactivation. The efficacy of Treg therapy is limited by the poor persistence of infused Tregs due to insufficient IL-2, which is essential for Treg survival and function. IL-2 activates many immune cells besides Tregs, imposing a challenge for the selective provision of IL-2 to infused Tregs. In this study, we found infusions of orthogonal (ortho) IL-2 failed to enhance Tregs engineered with a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. We then developed a receptor-tethered orthoIL-2 by optimizing the combination of IL-2, IL-2R, and the linker connecting them to achieve autocrine signaling selectively in engineered Tregs. Tregs expressing the tethered orthoIL-2 showed autocrine IL-2 signaling in vitro, enhanced CD25, CTLA-4, and Foxp3 expression, persisted without exogenous IL-2 in vivo, and prevented autoimmune diabetes using as few as 2,000 Tregs. Knocking the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific expression, with the additional benefit of positively reinforcing tethered orthoIL-2 expression through the activation of the Foxp3 gene by enhanced IL-2 signaling. Together, these results illustrate a safe and effective cell-engineering solution for overcoming Tregs’ dependency on exogenous IL-2, thereby achieving superior therapeutic efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE285527 | GEO | 2026/07/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Bach2 attenuates IL-2R signalling to control Treg homeostasis and Tfr development

Project description:Differentiation and homeostasis of Foxp3 + regulatory T cells (Tregs) are tightly controlled by the interleukin-2 receptor (IL-2R) signaling, yet the mechanisms governing these processes are incompletely understood. Here we report that transcription factor Bach2 attenuates IL-2R signaling to coordinate Treg differentiation and homeostasis by directly repressed CD25 (IL-2Rα). Thus, Bach2 balances IL-2R signaling to orchestrate development and homeostasis of various Treg subsets.

2021-05-11 | GSE164937 | GEO

The chromatin-modifying enzyme Ezh2 is a CD28-dependent molecule critical for the maintenance of Treg identity

Project description:Regulatory T cells (Tregs) are essential for maintaining proper immune homeostasis. Extracellular signals (e.g. TCR, CD28, IL-2R) are necessary for the generation and maintenance of Tregs, but how these signals are integrated to control the gene expression patterns of Tregs is less clear. Here we show that the epigenetic regulator, Ezh2, was induced by CD28 costimulation and Ezh2 activity was elevated in Tregs as compared to conventional CD4+ T cells. Deletion of Ezh2 in mouse Tregs led to a progressive autoimmune disease because Tregs were compromised after activation, losing proper control of essential Treg lineage genes and adopting a gene expression pattern similar to Foxp3-deficient ‘Tregs.’ Lineage-tracing of Ezh2-deficient Tregs in vivo confirmed that the cells were destabilized selectively in activated Treg populations, which led to a significant loss of Tregs in non-lymphoid tissues. These studies reveal an essential role for Ezh2 in the maintenance of Treg “identity” during cellular activation and differentiation. RNAseq of sorted populations of CD62Lhi or CD62Llo Tregs for both Ezh2-HET (Foxp3YFP-Cre/Foxp3WT;Ezh2fl/+ female mice) and Ezh2-KO (Foxp3YFP-Cre/Foxp3WT;Ezh2fl/fl female mice) were generated, in triplicate for each condition, using Illumina HiSeq 2500 single-end 50bp sequencing platform.

2015-02-09 | E-GEOD-58998 | biostudies-arrayexpress

A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance[TCR-seq]

Project description:STAT5 activation downstream of the Interleukin-2 receptor (IL-2R) facilitates Foxp3 expression, which is required for the differentiation and function of regulatory T (Treg) cells. However, due to the pleiotropic roles of IL-2R signaling, it is unclear how STAT5 acts on the Foxp3 locus to promote Treg cell lineage commitment. Here, we report that IL-2–STAT5 signaling converges on an enhancer (CNS4) during early Foxp3 induction. CNS4 facilitates and sustains the IL-2–dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency results in markedly impaired Treg cell generation in neonates, which is partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and, cooperatively with other tolerance mechanisms, minimizes autoimmunity.

2021-03-16 | GSE164117 | GEO

A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance[ChIP-seq][Stat5]

2021-03-16 | GSE163760 | GEO

Efficient IL-2R signaling differentially affects stability, function, and composition of the regulatory T cell pool

Project description:Signaling via the interleukin 2 receptor (IL-2R) is a requisite for Treg cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function during both resting and inflammatory conditions. Here, we characterized a spontaneous mouse mutant endowed with a hypomorphic Tyr129His variant of CD25, the a chain of the IL 2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under non-inflammatory conditions Cd25-Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune diseases. In contrast, Cd25-Y129H Treg cells failed to efficiently induce immune suppression and lost linage commitment in a T cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with maintenance, heterogeneity and suppressive function of the regulatory T cell pool.

2021-01-15 | GSE161345 | GEO

A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance [RNA-seq]

Project description:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.

2021-03-16 | GSE168829 | GEO

A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance

2021-03-16 | GSE168942 | GEO

A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance [ATAC-Seq]

2021-03-17 | GSE169043 | 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

The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation

2015-02-09 | GSE58998 | GEO