IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA454663 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7092901_1.fastq.gz | Fastqsanger.gz | |||
| SRR7092901_2.fastq.gz | Fastqsanger.gz | |||
| SRR7092902_1.fastq.gz | Fastqsanger.gz | |||
| SRR7092902_2.fastq.gz | Fastqsanger.gz | |||
| SRR7092903_1.fastq.gz | Fastqsanger.gz |
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Project description:Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.
2018-08-27 | GSE113951 | GEO
Project description:Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.
| S-EPMC6200646 | biostudies-literature
Project description:CD25 (IL-2R) can be expressed on the surface of immune cells in the absence of other chains of the interleukin-2 receptor (IL-2R), which are indispensable for IL-2 signaling. We identified two novel mast cell subsets, characterized by the differential expression of surface CD25, and by the ability to produce different cytokines and to proliferate, both in vitro and in vivo. We provide evidence that functional differences between the two mast cell populations were dependent on CD25 itself, which directly modulated mast cell proliferation and responses in vivo. These effects were completely independent from IL-2 or the expression of the other chains of the high-affinity IL-2R, indicating an autonomous and previously unappreciated role for CD25 in regulating cell functions. Similar results were also obtained in dendritic cells, which are known to express CD25 but to be unresponsive to IL-2. Our findings indicate a general role for CD25 in contexts where IL-2 signaling is not involved, and may have important implications for all mast cell-related diseases, including mastocytosis, where CD25 is aberrantly expressed on pathogenic mast cells. Total mRNA of FACS-sorted CD25pos and CD25neg populations of primary bone marrow-derived mast cells (BMMCs) was extracted and subjected to by multiparallel sequencing.
2014-08-03 | E-GEOD-52502 | biostudies-arrayexpress
Project description:CD25 (IL-2R) can be expressed on the surface of immune cells in the absence of other chains of the interleukin-2 receptor (IL-2R), which are indispensable for IL-2 signaling. We identified two novel mast cell subsets, characterized by the differential expression of surface CD25, and by the ability to produce different cytokines and to proliferate, both in vitro and in vivo. We provide evidence that functional differences between the two mast cell populations were dependent on CD25 itself, which directly modulated mast cell proliferation and responses in vivo. These effects were completely independent from IL-2 or the expression of the other chains of the high-affinity IL-2R, indicating an autonomous and previously unappreciated role for CD25 in regulating cell functions. Similar results were also obtained in dendritic cells, which are known to express CD25 but to be unresponsive to IL-2. Our findings indicate a general role for CD25 in contexts where IL-2 signaling is not involved, and may have important implications for all mast cell-related diseases, including mastocytosis, where CD25 is aberrantly expressed on pathogenic mast cells.
2014-08-03 | GSE52502 | GEO
Project description:CD25 monoclonal antibody binding to the alpha-chain of the Interleukin-2 (IL-2) receptor, blocks high affinity IL-2 binding thereby preventing complete T cell activation and being of ample importance in transplantation medicine and potentially the treatment of autoimmune disease. However, CD25 antibodies do not only block T cell activation but also prevent activation induced cell death (AICD) attributing a dual function to IL-2. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of humanized anti-CD25 mAb was investigated. PBMC were stimulated with CD3 antibody OKT-3 together with recombinant IL-2 in the absence or presence of anti-CD25 mAb. RNA was extracted and subjected to microarray analysis on U133A microarrays (Affymetrix). The expression profile revealed the up-regulation of 62 genes and down-regulation of 38 genes by anti-CD25 mAb, respectively.
2009-05-02 | GSE15928 | GEO
Project description:CD25 monoclonal antibody binding to the alpha-chain of the Interleukin-2 (IL-2) receptor, blocks high affinity IL-2 binding thereby preventing complete T cell activation and being of ample importance in transplantation medicine and potentially the treatment of autoimmune disease. However, CD25 antibodies do not only block T cell activation but also prevent activation induced cell death (AICD) attributing a dual function to IL-2. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of humanized anti-CD25 mAb was investigated. PBMC were stimulated with CD3 antibody OKT-3 together with recombinant IL-2 in the absence or presence of anti-CD25 mAb. RNA was extracted and subjected to microarray analysis on U133A microarrays (Affymetrix). The expression profile revealed the up-regulation of 62 genes and down-regulation of 38 genes by anti-CD25 mAb, respectively. Experiment Overall Design: Peripheral blood mononuclear cells (PBMC) were stimulated for 8 or 16 hrs with 100 ng/ml OKT-3 together with 100 U/ml recombinant human interleukin-2 (rhIL-2) in the absence or presence of 30 µg/ml anti-CD25 antibody. RNA from cells under such treatment was isolated with Trizol and subjected to microarray analysis onto human U133A microarray following the Affymetrix protocol.
2009-05-11 | E-GEOD-15928 | biostudies-arrayexpress
Project description:The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type-specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type-specific fashion.
2024-12-03 | GSE283392 | GEO
Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.
2024-01-26 | PXD044740 | Pride
Project description:MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [ATAC-Seq]
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Project description:MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [scRNA-Seq]
| PRJNA905813 | ENA