ArticleJournal of immunology (Baltimore, Md. : 1950)2015
Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region.
Article in Journal of immunology (Baltimore, Md. : 1950), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
57 citing papers in PubMed, 102 citations in OpenAlex.
- Regulatory T cells: From Foxp3 to tolerance-inducing therapies.The Journal of investigative dermatology · 2026Review
- TGF-β signaling mediates crosstalk between CD8Journal of biomedical science · 2026Article
- Structural and functional analysis of the TGF-β mimic, TGM-2: an immunomodulatory helminth protein.Genes and immunity · 2026Article
- Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives.Frontiers in immunology · 2026Review
- Multidimensional regulatory mechanisms and translational potential of epigenetic networks in the rheumatoid arthritis disease course.Frontiers in immunology · 2026Review
- Regulatory T cells in intracerebral hemorrhage: mechanisms of immunomodulation and therapeutic potential.Frontiers in immunology · 2026Review
- Regulatory T cells in homeostasis and disease: molecular mechanisms and therapeutic potential.Signal transduction and targeted therapy · 2025Review
- Review
- The Effect of Boric Acid and Calcium Fructoborate on T Helper Cell Differentiation by Influencing Foxp3 and Ror-γt in Rheumatoid Arthritis and Systemic Lupus Erythematosus.Biological trace element research · 2025Article
- Transcriptional fingerprinting of regulatory T cells: ensuring quality in cell therapy applications.Frontiers in immunology · 2025Article
- Methylation of T and B Lymphocytes in Autoimmune Rheumatic Diseases.Clinical reviews in allergy & immunology · 2024Review
- Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches.Stem cell reviews and reports · 2024Review
- Micronutrient regulation of the DNA methylome.Frontiers in epigenetics and epigenomics · 2024Review
- Adoptive TScience advances · 2023Article
- Changes in the gut microbiota of NOD mice in response to an oral Salmonella-based vaccine against type 1 diabetes.PloS one · 2023Article
- Article
- Evaluation of Th17 and Treg cytokines in patients with unexplained recurrent pregnancy loss.Journal of clinical and translational research · 2022Article
- Short-Chain Fatty Acids Augment Differentiation and Function of Human Induced Regulatory T Cells.International journal of molecular sciences · 2022Article
- Improving the Efficacy of Regulatory T Cell Therapy.Clinical reviews in allergy & immunology · 2022Review
- Regulatory T cells in ischemic stroke.Acta pharmacologica Sinica · 2022Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Regulatory T cell (Treg) therapy is a promising approach for transplant rejection and severe autoimmunity. Unfortunately, clinically meaningful Treg numbers can be obtained only upon in vitro culture. Functional stability of human expanded (e)Tregs and induced (i)Tregs has not been thoroughly addressed for all proposed protocols, hindering clinical translation. We undertook a systematic comparison of eTregs and iTregs to recommend the most suitable for clinical implementation, and then tested their effectiveness and feasibility in rheumatoid arthritis (RA). Regardless of the treatment, iTregs acquired suppressive function and FOXP3 expression, but lost them upon secondary restimulation in the absence of differentiation factors, which mimics in vivo reactivation. In contrast, eTregs expanded in the presence of rapamycin (rapa) retained their regulatory properties and FOXP3 demethylation upon restimulation with no stabilizing agent. FOXP3 demethylation predicted Treg functional stability upon secondary TCR engagement. Rapa eTregs suppressed conventional T cell proliferation via both surface (CTLA-4) and secreted (IL-10, TGF-β, and IL-35) mediators, similarly to ex vivo Tregs. Importantly, Treg expansion with rapa from RA patients produced functionally stable Tregs with yields comparable to healthy donors. Moreover, rapa eTregs from RA patients were resistant to suppression reversal by the proinflammatory cytokine TNF-α, and were more efficient in suppressing synovial conventional T cell proliferation compared with their ex vivo counterparts, suggesting that rapa improves both Treg function and stability. In conclusion, our data indicate Treg expansion with rapa as the protocol of choice for clinical application in rheumatological settings, with assessment of FOXP3 demethylation as a necessary quality control step.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.