Durable control of autoimmunity requires sustained stimulation of regulatory T cells [TCR scRNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE312449 | GEO | 2026/03/30
REPOSITORIES: GEO
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Project description:Low-dose recombinant interleukin-2 (rIL-2) therapy holds significant promise for treating autoimmune and inflammatory disorders by selectively expanding the endogenous pool of CD4⁺Foxp3⁺ regulatory T cells (Tregs). However, clinical benefits are limited by the suboptimal pharmacokinetic profile of rIL-2, which fails to support sustained Treg activation. Here we investigated the efficacy of a long-lasting IL-2-based biologic mIL-2/CD25 to limit type 1 diabetes in female NOD mice when administered in a manner to cause periodic versus continual increases in Tregs. We find that the latter is highly effective in limiting autoimmunity and leads to substantial remodeling of the pancreatic islet immune landscape, which has important implications for advancing IL-2-based therapies for autoimmunity.
2026-03-30 | GSE300669 | 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.
2018-08-27 | GSE113951 | GEO
Project description:We report gene expression of Treg cells isolated from injured muscle in IL-33 vs PBS treated mice. Male Foxp3-GFP C57BL/6 reporter (2 months old) mice were injured intramuscularly with cardiotoxin/rIL-33 (0.3 ug/muscle). Tregs were sorted directly into Trizol from injured muscle 4 days post-injury. Gene expression profiling of muscle Tregs from IL-33 vs PBS injured mice.
2016-01-12 | E-GEOD-76722 | biostudies-arrayexpress
Project description:Transplantation is the preferred treatment for most patients with end-stage organ disease, but long-term outcomes are hindered by immunosuppressive drug toxicity and immune-mediated injury. Developing therapies that promote immune tolerance while minimizing systemic immunosuppression is essential to improve graft health and survival. Regulatory T cell (Treg)-based therapies offer promise for inducing antigen-specific transplant tolerance, with recombinant IL-2 analogs emerging as potentially effective tools to selectively expand Tregs while minimizing adverse effects. mIL-2 therapy combined with co-stimulation blockade significantly prolonged allograft survival in an antigen-specific manner without adverse events. The immunomodulatory effects of mIL-2 persisted even after treatment cessation at 60 days after transplantation, with sustained graft function and preservation of histopathological integrity. Treatment with mIL-2 increased graft-infiltrating Tregs and decreased effector T cell activation. Donor-specific antibody production was reduced in mIL-2-treated recipients, which correlated with an enhanced follicular regulatory T-cell proportion. These findings were consistent across fully mismatched kidney and haplo-mismatched heart transplant models. Transcriptional profiling revealed the expansion of an ST2-positive, tissue-resident Treg population critical for long-term graft survival. Accordingly, the mIL-2-induced Treg suppression was abrogated in Treg-specific ST2 knockout graft recipients.
2025-01-27 | GSE287628 | GEO
Project description:We report gene expression of Treg cells isolated from injured muscle in IL-33 vs PBS treated mice. Male Foxp3-GFP C57BL/6 reporter (2 months old) mice were injured intramuscularly with cardiotoxin/rIL-33 (0.3 ug/muscle). Tregs were sorted directly into Trizol from injured muscle 4 days post-injury.
2016-01-12 | GSE76722 | GEO
Project description:Regulatory T cells (Tregs) are necessary for the maintenance of immune self-tolerance and homeostasis. They have a heightened sensitivity to IL-2, which may create a therapeutic window to promote immune regulation by their selective stimulation. While IL-2 responsive genes are well characterized, yet remain unknown genetic, chromatin and metabolic programs during sustained IL-2R signaling. Longitudinal transcriptional and chromatin accessibility profiling and metabolic studies were performed on peripheral Tregs in response to long-lived mIL-2/CD25 fusion protein. We found an initially increased STAT5 dependent gene modulation enabled by enhanced chromatin accessibility, whereas a STAT5-independent genome-wide chromatin closing to inhibit transcription and cell signaling occurred later. Interestingly, IL-2-dependent genes were induced upon re-stimulation. Mitochondrial metabolism was reprogrammed to fulfill the bioenergetics demand for the burst of proliferation. We propose that a shift from euchromatin to heterochromatin represents a mechanism to restrain, but not abrogate, persistent IL-2R signaling to maintain Treg homeostasis.
2022-02-16 | GSE162030 | GEO
Project description:Regulatory T cells (Tregs) are necessary for the maintenance of immune self-tolerance and homeostasis. They have a heightened sensitivity to IL-2, which may create a therapeutic window to promote immune regulation by their selective stimulation. While IL-2 responsive genes are well characterized, yet remain unknown genetic, chromatin and metabolic programs during sustained IL-2R signaling. Longitudinal transcriptional and chromatin accessibility profiling and metabolic studies were performed on peripheral Tregs in response to long-lived mIL-2/CD25 fusion protein. We found an initially increased STAT5 dependent gene modulation enabled by enhanced chromatin accessibility, whereas a STAT5-independent genome-wide chromatin closing to inhibit transcription and cell signaling occurred later. Interestingly, IL-2-dependent genes were induced upon re-stimulation. Mitochondrial metabolism was reprogrammed to fulfill the bioenergetics demand for the burst of proliferation. We propose that a shift from euchromatin to heterochromatin represents a mechanism to restrain, but not abrogate, persistent IL-2R signaling to maintain Treg homeostasis.
2022-02-16 | GSE163946 | GEO
Project description:This is system 2, the model with Michelis Menten type antigen uptake by pAPCs, described in the article:
Self-tolerance and Autoimmunity in a Regulatory T Cell Model.
Alexander HK, Wahl LM. Bull Math Biol.
2010 Mar 2.
PMID: 20195912
, doi: 10.1007/s11538-010-9519-2
;
Abstract:
The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R (0) for each system. When R (0) 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach).
Originally created by libAntimony v1.4 (using libSBML 3.4.1)
2024-09-02 | BIOMD0000000290 | BioModels
Project description:This is system 1, the model with linear antigen uptake by pAPCs, described in the article:
Self-tolerance and Autoimmunity in a Regulatory T Cell Model.
Alexander HK, Wahl LM.
Bull Math Biol. 2010 Mar 2.
PMID:20195912, doi:10.1007/s11538-010-9519-2;
Abstract:
The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R (0) for each system. When R (0) 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach).
Originally created by libAntimony v1.4 (using libSBML 3.4.1)
2024-09-02 | BIOMD0000000289 | BioModels
Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs. RNA was isolated using RNeasy kits (QIAGEN), and RNA integrity and quantity were analyzed by NanoDrop ND-1000 and Nanochip 2100 Bioanalyzer (Agilent Technologies). Microarray experiments were performed using whole mouse genome oligoarrays (Mouse430a, Affymetrix) and array data analyzed using MAYDAY 2.12 software. Array data were subjected to robust multiarray average (RMA) normalization and analyzed using Student’s t test. Only data with a false discovery rate-adjusted P value of less than 0.05 and at least 2× differential expression were included in the analysis. Data underwent z-score transformation for display.
2015-05-19 | E-GEOD-68991 | biostudies-arrayexpress