ArticleImmunity2021
Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.
Article in Immunity, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 2 of them syntheses that pooled it.
What it found
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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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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
82 citing papers in PubMed, 2 syntheses or guidelines pooled it, 119 citations in OpenAlex.
- Meta-analysis of Transcriptomic Data from Lung Autopsy and Cellular Models of SARS-CoV-2 Infection.Biochemical genetics · 2024Pooled it
- Pooled it
- Genetic factors associated with COVID-19 severity and mortality: TYK2 and NOTCH4.Biomedical reports · 2026Article
- Beyond immune suppression: regenerative programs in regulatory T cells.Cell insight · 2026Review
- Sex-specific trajectories of nonlinear immune aging at single-cell level.Nature communications · 2026Article
- Regulation of mCell biology and toxicology · 2026Review
- Decoding Treg diversity and dysfunction to advance Treg-based therapies in autoimmune and inflammatory diseases.Frontiers in immunology · 2026Review
- Editorial: The transcriptional and metabolic role of Foxp3 in regulatory T cells.Frontiers in immunology · 2026Article
- Characterization of the SARS-CoV-2-Specific T Cell Responses in Rheumatoid Arthritis Subjects Vaccinated for COVID-19 Protection.European journal of immunology · 2025Article
- Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis.Immunity · 2025Article
- CXCR1 Depletion in Ly6CAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells.Nature immunology · 2025Article
- The long reach of influenza and other respiratory viruses: from acute epithelial injury to post-viral lung disease.Clinical microbiology reviews · 2025Review
- Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.Immunity · 2025Article
- T Regulatory Mechanisms in Airway and Interstitial Lung Disease.Seminars in respiratory and critical care medicine · 2025Review
- An amphiregulin reporter mouse enables transcriptional and clonal expansion analysis of reparative lung Tregs.JCI insight · 2025Article
- Machine Learning Reveals the Value of Unconventional T Lymphocytes in Sepsis and Prognosis of Elderly Patients With Severe Lower Respiratory Tract Infections.Journal of clinical laboratory analysis · 2025Article
- Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion.Molecular metabolism · 2025Article
- Association of elevated Delta-like canonical Notch ligand 1 levels with clinical outcomes in patients hospitalized for SARS-CoV2 infection.Scientific reports · 2025Observational
- Single-cell and chromatin accessibility profiling reveals regulatory programs of pathogenic Th2 cells in allergic asthma.Nature communications · 2025Article
22 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
33 authors at 8 institutions in 5 countries.
Funding
Abstract
A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
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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.