ArticleArthritis & rheumatology (Hoboken, N.J.)2014
Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 106 citations in OpenAlex.
- Therapeutic potential of targeting Tfr/Tfh cell balance by low-dose-IL-2 in active SLE: a post hoc analysis from a double-blind RCT study.Arthritis research & therapy · 2021Trial
- High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults.Frontiers in immunology · 2018Trial
- IL-6-induced C/EBPα drives follicular regulatory T cell differentiation to regulate humoral immunity in mice.Nature communications · 2026Article
- Methylprednisolone Modulates the Tfr/Tfh ratio in EAE-Induced Neuroinflammation through the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR Signalling Pathways.Inflammation · 2025Article
- T-cell help in the germinal center: homing in on the role of IL-21.International immunology · 2024Article
- FGL1-LAG3 axis impairs IL-10-Producing regulatory T cells associated with Systemic lupus erythematosus disease activity.Heliyon · 2023Article
- T follicular helper cells and T follicular regulatory cells in autoimmune diseases.Frontiers in immunology · 2023Review
- The SYSCID map: a graphical and computational resource of molecular mechanisms across rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease.Frontiers in immunology · 2023Article
- Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R.International journal of molecular sciences · 2022Article
- T cell help in the autoreactive germinal center.Scandinavian journal of immunology · 2022Review
- Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis.Frontiers in immunology · 2022Article
- Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes.Diabetes · 2021Article
- The Germinal Center Milieu in Rheumatoid Arthritis: The Immunological Drummer or Dancer?International journal of molecular sciences · 2021Review
- Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases.Inflammation and regeneration · 2021Review
- Frontiers of Autoantibodies in Autoimmune Disorders: Crosstalk Between Tfh/Tfr and Regulatory B Cells.Frontiers in immunology · 2021Review
- Regulation of antibody responses against self and foreign antigens by Tfr cells: implications for vaccine development.Oxford open immunology · 2021Review
- Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2021Article
- Follicular Regulatory T Cells in Systemic Lupus Erythematosus.Journal of immunology research · 2021Review
- SLAM/SAP Decreased Follicular Regulatory T Cells in Patients with Graves' Disease.Journal of immunology research · 2021Observational
- The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren's Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution.Frontiers in immunology · 2021Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
objectiveFollicular regulatory T (Tfr) cells act as the regulatory counterpart of follicular helper T (Tfh) cells to suppress germinal center (GC) B cell differentiation. We recently showed that interleukin-21 (IL-21) promoted Tfh cell differentiation in autoimmune BXD2 mice that develop spontaneous GCs. This study was undertaken to determine the modulatory effects of IL-21 on Tfr cells and the Tfr cell to Tfh cell balance in BXD2 mice.
methodsThe percentage and phenotype of Tfr cells were determined in BXD2 and BXD2-IL21(-/-) mice. The effects of IL-21 on Tfr cells and the Tfr cell:Tfh cell ratio were evaluated. Sorted Tfr cells from BXD2-IL21(-/-) mice were cocultured with Tfh cells and B cells, or transferred into BXD2 mice to determine their function.
resultsThe percentages and numbers of GC B cells and Tfh cells were significantly reduced, but the percentage of Tfr cells was 2-fold higher in BXD2-IL21(-/-) mice than in wild-type BXD2 mice. Administration of AdIL-21 to BXD2-IL21(-/-) mice decreased the percentages and numbers of Tfr cells and the Tfr cell:Tfh cell ratio but increased the number of GC B cells in the spleen. Recombinant murine IL-21 suppressed FoxP3 and significantly reduced Tgfb1, Il2, and Gitr but enhanced Il21, Il6, Pd1, Cxcr5, and Icos expression in Tfr cells. IL-21 also counteracted Tfr cell-mediated inhibition of antibody secretion in the Tfh cell-B cell coculture system. Transfer of Tfr cells into young BXD2 mice reduced GC size and decreased the numbers of autoantibody-producing B cells.
conclusionOur findings indicate that high levels of IL-21 selectively enhance Tfh cell differentiation but inhibit Tfr cell commitment and the suppressive function of Tfr cells on Tfh cells and B cells, suggesting that IL-21 skews the balance from Tfr cells to Tfh cells to promote autoreactive GC reactions in BXD2 mice.
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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.