ArticleJournal of immunology (Baltimore, Md. : 1950)2015
Transmembrane TNF-TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression.
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 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- Tumor necrosis factor inhibitor-related autoimmune disorders in pediatric rheumatology practice: a multicenter nationwide study.Pediatric rheumatology online journal · 2026Article
- Promising TNF-α inhibitors: Targeting pathogenic TNF-α/TNFR signaling to restore Th17/Treg balance in rheumatoid arthritis.Journal of pharmaceutical analysis · 2026Review
- Therapeutic Potential of Polyphenols in Targeting Th17/Treg Balance for Intestinal Barrier Maintenance.Food science & nutrition · 2025Review
- Inflammation and cancer cell survival: TRAF2 as a key player.Cell death & disease · 2025Review
- Tumor necrosis factor receptor 2 in allergen tolerance: a perspective view.Frontiers in immunology · 2025Review
- Cancer marker TNFRSF1A: From single‑cell heterogeneity of renal cell carcinoma to functional validation.Oncology letters · 2024Article
- Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers.Translational oncology · 2022Article
- TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation.Frontiers in immunology · 2022Review
- TRIMs: selective recruitment at different steps of the NF-κB pathway-determinant of activation or resolution of inflammation.Cellular and molecular life sciences : CMLS · 2021Review
- Insights into the biology and therapeutic implications of TNF and regulatory T cells.Nature reviews. Rheumatology · 2021Review
- TNFR2: Role in Cancer Immunology and Immunotherapy.ImmunoTargets and therapy · 2021Review
- From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis.Frontiers in pharmacology · 2021Review
- Complexity of TNF-α Signaling in Heart Disease.Journal of clinical medicine · 2020Review
- Selective Targeting of TNF Receptors as a Novel Therapeutic Approach.Frontiers in cell and developmental biology · 2020Review
- TNFR2 limits proinflammatory astrocyte functions during EAE induced by pathogenic DR2b-restricted T cells.JCI insight · 2019Article
- TNF receptor 2 signaling prevents DNA methylation at theProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis.Brain, behavior, and immunity · 2019Article
- TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Inflammatory Responses Reprogram TScientific reports · 2019Article
- Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4Cell death & disease · 2019Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The double-edged sword nature by which IL-2 regulates autoimmunity and the unpredictable outcomes of anti-TNF therapy in autoimmunity highlight the importance for understanding how TNF regulates IL-2. Transmembrane TNF (tmTNF) preferentially binds TNFR2, whereas soluble TNF (sTNF) binds TNFR1. We previously showed reduced IL-2 production in TNFR1(-/-) TNFR2(-/-) CD4(+) T cells. In this study, we generated TNFR1(-/-), TNFR2(-/-), or TNFR1(-/-) TNFR2(-/-) 5C.C7 TCR Il2-GFP mice and report that CD4(+) T cell-intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. We further used tmTNF Foxp3 gfp reporter mice and pharmacological TNF blockade in wild-type mice to report a tmTNF/TNFR2 interaction for Il2 expression. IL-17 is critical for host defense, but its overabundance promotes autoimmunity. IL-2 represses Th17 differentiation, but the role for TNFR2 in this process is not well understood. We report elevated expression of TNFR2 under Th17-polarization conditions. Genetic loss-of-function experimental models, as well as selective TNF blockade by etanercept and XPro1595 in wild-type mice, demonstrate that impaired tmTNF/TNFR2, but not sTNF/TNFR1, promotes Th17 differentiation in vivo and in vitro. Under Th17-polarizing conditions, elevated IL-17 production by TNFR2-knockout CD4(+) T cells was associated with increased STAT3 activity and decreased STAT5 activity. Increased IL-17 production in TNFR2-knockout T cells was prevented by adding exogenous IL-2. We conclude that CD4(+) T cell-intrinsic tmTNF/TNFR2 promotes IL-2 production that inhibits the generation of Th17 cells in a Foxp3-independent manner. Moreover, under Th17-polarizing conditions, selective blockade of CD4(+) T cell-intrinsic TNFR2 appears to be sufficient to promote Th17 differentiation.
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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.