ArticleJCI insight2023
TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 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.
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Who cites it
10 citing papers in PubMed, 14 citations in OpenAlex.
- Differential transcriptional and epigenetic signatures in CD4Journal of translational autoimmunity · 2026Article
- Emerging mechanistic trends and clinical efficacy for methotrexate: Applications to inflammatory bowel disease.Pharmacological reviews · 2026Review
- The Role and Mechanistic Effects of Methotrexate in the Treatment of Rheumatoid Arthritis.European journal of rheumatology · 2025Article
- Low Dose Methotrexate Has Divergent Effects on Cycling and Resting Human Hematopoietic Stem and Progenitor Cells.Clinical and translational science · 2025Article
- Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases.Frontiers in immunology · 2025Review
- The 'TNature reviews. Rheumatology · 2025Review
- Stage-specific GATA3 induction promotes ILC2 development after lineage commitment.Nature communications · 2024Article
- Micronutrient regulation of the DNA methylome.Frontiers in epigenetics and epigenomics · 2024Review
- Review
- New T cell target of methotrexate identified.Nature reviews. Rheumatology · 2023Article
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA); however, its precise mechanisms of action other than antifolate activity are largely unknown. We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment. TAp63, an isoform of TP63, was highly expressed in human IL-17-producing Th (Th17) cells and was suppressed by MTX in vitro. Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model. RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene. TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells. Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells. Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer. Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.
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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 Socratic graph.