ArticleThe Journal of clinical investigation2022
SMAD4 TGF-β-independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 29 citations in OpenAlex.
- Cellular crosstalk of fibroblast-myofibroblast transition in intestinal homeostasis and disease.Biomarker research · 2026Review
- The roles and heterogeneity of CD8International journal of molecular medicine · 2026Review
- eQTL in diseased colon tissue identifies potential target genes associated with IBD.Nature communications · 2026Article
- Daily intermittent fasting is an effective multiscale treatment in preclinical models of absence epilepsy.Epilepsia · 2026Article
- Identification and characterization of a TGF-β-independent SMAD4-NFATc1-STAT3 regulatory axis.Journal of molecular cell biology · 2026Article
- Smad4 and Eomes converge on a shared transcriptional program associated with inflammatory CD8 T-cell differentiation.Frontiers in immunology · 2026Article
- The Dynamic Regulation of Daxx-Mediated Transcriptional Inhibition by SUMO and PML NBs.International journal of molecular sciences · 2025Review
- A role for TGFβ signaling in Gli1+ tendon and enthesis cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Addressing the Role of Conventional CD8αβ+ T Cells and CD4+ T Cells in Intestinal Immunopathology Using a Bone Marrow-Engrafted Model.Bio-protocol · 2024Article
- SMAD4 enhances the cytotoxic efficacy of human NK cells against colorectal cancer cells via the mFrontiers in immunology · 2024Article
- CircLDLRAD3 inhibits Oral squamous cell carcinoma progression by regulating miR-558/Smad4/TGF-β.Journal of cellular and molecular medicine · 2023Article
- TGF-β signaling in health and disease.Cell · 2023Review
- Transforming Growth Factor Beta Promotes Inflammation and Tumorigenesis in Smad4-Deficient Intestinal Epithelium in a YAP-Dependent Manner.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- TGFβ control of immune responses in cancer: a holistic immuno-oncology perspective.Nature reviews. Immunology · 2023Review
- Myeloid vitamin D receptor regulates Paneth cells and microbial homeostasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Review
- The diverse effects of transforming growth factor-β and SMAD signaling pathways during the CTL response.Frontiers in immunology · 2023Review
- Editorial: TGF-β and T cell biology.Frontiers in immunology · 2023Article
- The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma.Frontiers in medicine · 2023Article
- TGF-beta signal transduction: biology, function and therapy for diseases.Molecular biomedicine · 2022Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SMAD4, a mediator of TGF-β signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using both genetic and epigenetic approaches, we revealed an unexpected mechanism by which SMAD4 prevents naive CD8+ T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-β receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-β signature in naive CD8+ T cells. Mechanistically, prior to TGF-β signaling, SMAD4 binds to promoters and enhancers of several TGF-β target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-β signal, SMAD4 limits the expression of TGF-β negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-β. In addition, SMAD4 ablation conferred naive CD8+ T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-β control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-β-independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.
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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.