Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis

CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.

• Publication year

  2004

• Venue

  Journal of Experimental Medicine

• Publication date

  2004-04-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20031579PMID 15067033PMCID 2211881
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Regulatory T cells

  2006cited by this paper
• Role of ICAM-1 and P-selectin expression in the development and effector function of CD4+CD25+regulatory T cells.

  2003cited by this paper
• Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells

  2003cited by this paper
• EncephalomyelitisExperimental Autoimmune System Inflammation During Active Immune Responses and Central Nervous Cells Suppress Antigen-Specific Autoreactive Regulatory T + CD25+ Cutting Edge: CD4

  2002cited by this paper
• The Subpopulation of CD4+CD25+ Splenocytes That Delays Adoptive Transfer of Diabetes Expresses L-Selectin and High Levels of CCR71

  2002cited by this paper
• GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes.

  2002cited by this paper
• Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects.

  2002cited by this paper
• Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy.

  2002cited by this paper
• Inhibition of Human CD4+CD25+high Regulatory T Cell Function1

  2002influential reference
• Faculty Opinions recommendation of GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes.

  2002cited by this paper
• Control of T‐cell activation by CD4+ CD25+ suppressor T cells

  2001cited by this paper
• Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function

  2001cited by this paper
• The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis

  2001cited by this paper
• Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro

  2001cited by this paper
• Ex Vivo Isolation and Characterization of Cd4+Cd25+ T Cells with Regulatory Properties from Human Blood

  2001cited by this paper
• Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS Lyme disease.

  2001cited by this paper
• CD4+CD25high Regulatory Cells in Human Peripheral Blood1

  2001cited by this paper
• Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation

  2000cited by this paper
• Regulatory T cells in autoimmmunity*.

  2000cited by this paper
• Regulatory T cells: key controllers of immunologic self-tolerance.

  2000cited by this paper
• B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes.

  2000cited by this paper
• CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells.

  1998cited by this paper
• Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation.

  1998cited by this paper
• CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production

  1998cited by this paper
• Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells.

  1998cited by this paper
• CD4+ T-cells in the regulation of inflammatory responses in the intestine.

  1997cited by this paper
• Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

  1995cited by this paper
• T-cell recognition of an immuno-dominant myelin basic protein epitope in multiple sclerosis

  1990cited by this paper
• T cell tolerance by clonal elimination in the thymus.

  1987cited by this paper
• Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease

  1985influential reference

• Bioactive Phytochemicals in Experimental Models of Multiple Sclerosis: Mechanisms, Efficacy, and Translational Potential

  2026cites this paper
• Purification, Phenotypic and Functional Analyses of Regulatory T Cells in Autoimmunity.

  2026cites this paper
• “The Interaction Between Oxidative Stress and Neurosteroid Imbalance in Multiple Sclerosis: Exploring a New Pathway in Disease Mechanisms and Potential Treatment Approaches”

  2026cites this paper
• Epigenomic profiling of cerebrospinal fluid cells identifies immune regulatory alterations and implicates protocadherins in multiple sclerosis

  2026cites this paper
• EBV and Autoimmunity.

  2025cites this paper
• Tregs epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity

  2025cites this paper
• Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases

  2025cites this paper
• Intersections Between Allergic Diseases and Multiple Sclerosis: Mechanisms, Clinical Implications, and Hypersensitivity Reactions to Therapy

  2025cites this paper
• Tissue-specific roles of regulatory T cells: mechanisms of suppression and beyond along with emerging therapeutic insights in autoimmune indications

  2025cites this paper
• Multiple sclerosis-like manifestations in systemic autoimmune and inflammatory disorders: an update

  2025cites this paper
• White Blood Cells in Neurodegenerative Diseases in the Context of Neuroinflammation

  2025cites this paper
• Transcriptomic profiling after B cell depletion reveals central and peripheral immune cell changes in multiple sclerosis

  2025cites this paper
• Loss of TET function in T regulatory cells yields ex-Treg cells biased toward T follicular helper cells, causing autoimmune diseases through autoantibody production

  2025cites this paper
• A Notch too far: Treg plasticity in multiple sclerosis.

  2025cites this paper
• Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis

  2025cites this paper
• Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis.

  2025cites this paper
• The TET-TDG axis in T cells and biological processes.

  2025cites this paper
• Inverse Vaccination for Autoimmune Diseases: Insights into the Role of B Lymphocytes

  2025cites this paper
• Proinflammatory Effect of Mesenchymal Stem Cells From Patients With Multiple Sclerosis

  2025influential citation
• Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity

  2025cites this paper
• A probiotic approach identifies a Treg-centred immunoregulation via modulation of gut microbiota metabolites in people with multiple sclerosis and healthy individuals

  2025cites this paper
• MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis.

  2025cites this paper
• Sex Bias in IL-10 Production by Type I Regulatory T Cells Regulated by PI3K/mTOR Signaling

  2025cites this paper
• Intravenous Immunoglobulin Elevates Regulatory T Cells in Guillain‐Barré Syndrome: A Potential Biomarker of Therapeutic Response

  2025cites this paper
• Therapeutic potentials of Trichinella spiralis in immune disorders: From allergy to autoimmunity

  2025cites this paper
• Redefining multiple sclerosis therapy through microbial immunomodulation and epigenetic control

  2025cites this paper
• The role of the adaptive immune system in the initiation and persistence of multiple sclerosis.

  2025cites this paper
• B cell tolerance checkpoint function in multiple sclerosis and transient CD52 depletion

  2025cites this paper
• Breaking Boundaries: Chronic Diseases and the Frontiers of Immune Microenvironments

  2025cites this paper
• The link between gut microbiota and multiple sclerosis from the perspective of barrier function

  2025cites this paper
• Prior murine neurotropic coronavirus infection ameliorates experimental autoimmune encephalitis.

  2025cites this paper
• Impaired PTEN Expression in T Cells Drives Resistance to Treg-Mediated Immune Regulation in Multiple Sclerosis

  2025cites this paper
• Nonclinical regulatory considerations for investigational new drug applications for regulatory T cell therapies

  2025cites this paper
• Host Genetic Architecture between Epstein–Barr Virus Activity and Multiple Sclerosis Reveals Shared Pathways

  2025cites this paper
• Vitamin D and Neurodegenerative Diseases Such as Multiple Sclerosis (MS), Parkinson’s Disease (PD), Alzheimer’s Disease (AD), and Amyotrophic Lateral Sclerosis (ALS): A Review of Current Literature

  2025cites this paper
• Metabolic reprogramming as a therapeutic target for modulating the Th17/Treg balance in autoimmune diseases: a comprehensive review

  2025cites this paper
• Regulatory T Cell Sub-Populations in Patients with Distinct Autoimmune/Inflammatory Diseases With or Without Inborn Errors of Immunity

  2025cites this paper
• Microecologics and Exercise: Targeting the Microbiota–Gut–Brain Axis for Central Nervous System Disease Intervention

  2025cites this paper
• High frequency of circulating non-classical monocytes is associated with stable remission in relapsing-remitting multiple sclerosis

  2024cites this paper
• Berberine: A natural modulator of immune cells in multiple sclerosis

  2024cites this paper
• Meta-analysis of the Selected Genetic Variants in Immune-Related Genes and Multiple Sclerosis Risk

  2024cites this paper
• Treated and Untreated Primary Progressive Multiple Sclerosis: Walkthrough Immunological Changes of Monocytes and T Regulatory Cells

  2024cites this paper
• 34-parameter full spectrum immunophenotyping panel of human regulatory and effector lymphocytes

  2024cites this paper
• Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis

  2024cites this paper
• The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases

  2024cites this paper
• Kv1.3 in the spotlight for treating immune diseases

  2024cites this paper
• Single-cell transcriptome landscape of circulating CD4+ T cell populations in autoimmune diseases

  2024cites this paper
• Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue

  2024cites this paper
• A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction

  2024cites this paper
• Single cell characterization of blood and expanded regulatory T cells in autoimmune polyendocrine syndrome type 1

  2024cites this paper
• Altered miR-10a gene expression in peripheral blood mononuclear cells correlates with frequency of T regulatory cells and cytokine profile in multiple sclerosis patients.

  2024cites this paper
• MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

  2024cites this paper
• Sphingosine-1-phosphate alleviates Sjögren's syndrome-like symptoms via inducing autophagy and regulating status of Treg cells in NOD mice.

  2024cites this paper
• The Role of Extracellular Vesicles and Microparticles in Central Nervous System Disorders: Mechanisms, Biomarkers, and Therapeutic Potential

  2024cites this paper
• Understanding Multiple Sclerosis Pathophysiology and Current Disease-Modifying Therapies: A Review of Unaddressed Aspects.

  2024cites this paper
• Role of the intestinal microbiota in the pathogenesis of multiple sclerosis. Part 3. Gut microbiota as a potential trigger for multiple sclerosis

  2024cites this paper
• Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair

  2024cites this paper
• Improving regulatory T cell production through mechanosensing.

  2024cites this paper
• An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction

  2024cites this paper
• The potential therapeutic role of IL-35 in pathophysiological processes in type 1 diabetes mellitus.

  2024cites this paper
• Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance

  2024cites this paper
• Alterations of Thymus-Derived Tregs in Multiple Sclerosis

  2024cites this paper
• Game of microbes: the battle within – gut microbiota and multiple sclerosis

  2024cites this paper
• MicroRNAs targeting TGF‐β signaling exacerbate central nervous system autoimmunity by disrupting regulatory T cell development and function

  2024cites this paper
• T Cell Subsets and Immune Homeostasis.

  2024cites this paper
• Emerging role of gut microbiota in autoimmune diseases

  2024cites this paper
• Targeted Therapy of Multiple Sclerosis: A Case for Antigen-Specific Tregs

  2024cites this paper
• Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis

  2024cites this paper
• Therapy with regulatory T-cell infusion in autoimmune diseases and organ transplantation: A review of the strengths and limitations.

  2024cites this paper
• Human chorionic gonadotropin regulates cytokine production by lymphocytes from patients with multiple sclerosis.

  2024cites this paper
• Dimethyl fumarate modulates the regulatory T cell response in the mesenteric lymph nodes of mice with experimental autoimmune encephalomyelitis

  2024cites this paper
• Immunoregulatory Effects of the Active Form of Vitamin D (Calcitriol), Individually and in Combination with Curcumin, on Peripheral Blood Mononuclear Cells (PBMCs) of Multiple Sclerosis (MS) Patients.

  2024cites this paper
• Modification of T- and B-cell-associated immuno-pathologic mechanisms in multiple sclerosis by disease modifying therapies: Achievements and opportunities.

  2024cites this paper
• Immune Dysregulation Orchestrated by High-Salt Diet: Mechanistic Insights into Disease Pathogenesis

  2024cites this paper
• Autophagy dysregulation plays a crucial role in regulatory T-cell loss and neuroinflammation in amyotrophic lateral sclerosis (ALS)

  2023cites this paper
• Multiple faces of multiple sclerosis in the era of highly efficient treatment modalities: Lymphopenia and switching treatment options challenges daily practice.

  2023cites this paper
• MAP kinase inhibitor PD98059 regulates Th1, Th9, Th17, and natural T regulatory cells in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

  2023cites this paper
• Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance

  2023cites this paper
• Interaction of the Gut Microbiome and Immunity in Multiple Sclerosis: Impact of Diet and Immune Therapy

  2023cites this paper
• Non-Coding RNAs as Potential Targets for Diagnosis and Treatment of Oral Lichen Planus: A Narrative Review

  2023cites this paper
• GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development

  2023cites this paper
• Novel role of GPR109A in thymic regulatory T cell development

  2023cites this paper
• Regulatory T cells in autoimmune primary adrenal insufficiency

  2023cites this paper
• Suppression of Experimental Autoimmune Encephalomyelitis in Mice by β-Hydroxy β-Methylbutyrate, a Body-Building Supplement in Humans.

  2023cites this paper
• The Function of T Cell Immunity in Lymphedema: A Comprehensive Review

  2023cites this paper
• Peripheral MC1R activation modulates immune responses and is neuroprotective in a mouse model of Parkinson’s disease

  2023cites this paper
• The Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?

  2023cites this paper
• Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis

  2023cites this paper
• Regulating the regulatory T cells as cell therapies in autoimmunity and cancer

  2023cites this paper
• Bibliometric analysis of global research trends on regulatory T cells in neurological diseases

  2023cites this paper
• Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system

  2023cites this paper
• Treg plasticity and human diseases

  2023cites this paper
• Dysregulated brain regulatory T cells fail to control reactive gliosis following repeated antigen stimulation

  2023cites this paper
• S3I-201, a selective stat3 inhibitor, ameliorates clinical symptoms in a mouse model of experimental autoimmune encephalomyelitis through the regulation of multiple intracellular signalling in Th1, Th17, and treg cells.

  2023cites this paper
• Anti-human-TIGIT agonistic antibody ameliorates autoimmune diseases by inhibiting Tfh and Tph cells and enhancing Treg cells

  2023cites this paper
• How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases?

  2023cites this paper
• FOXP3+ regulatory T cells use heparanase to access IL-2 bound to ECM in inflamed tissues

  2023cites this paper
• Comparison of OX40 expression in patients with multiple sclerosis and neuromyelitis optica as an approach to diagnosis

  2023cites this paper
• Single-cell transcriptome landscape of circulating CD4+ T cell populations in human autoimmune diseases

  2023cites this paper
• Contribution of survivin to the immune system, allergies and autoimmune diseases.

  2023cites this paper