ArticleThe Journal of clinical investigation2023
The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.
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Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19citing papers in PubMed
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Neurological and Neuropsychiatric Manifestations of Pediatric Inflammatory Multisystem Syndrome (PIMS/MIS-C): A Narrative Review.Journal of personalized medicine · 2026Review
- Screening of autoinflammatory genes in patients with SARS-CoV-2-associated MIS-C.Human genomics · 2026Article
- Editorial: The transcriptional and metabolic role of Foxp3 in regulatory T cells.Frontiers in immunology · 2026Article
- Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis.Immunity · 2025Article
- Immunological Mechanisms Underlying Allergy Predisposition After SARS-CoV-2 Infection in Children.Cells · 2025Review
- Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation.The Journal of experimental medicine · 2025Article
- Curcumin prevents dexamethasone-induced activation of the pseudorabies virus in rat pheochromocytoma cells through the miR-155-5p-Aak1-Numb/Notch2 signalling axis.Veterinary research · 2025Article
- Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).The Journal of experimental medicine · 2024Article
- Numb and NumbL inhibit melanoma tumor growth by influencing the immune microenvironment.BMC cancer · 2024Article
- 17β-estradiol inhibits Notch1 activation in murine macrophage cell line RAW 264.7.Molecular biology reports · 2024Article
- 1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit.International journal of molecular sciences · 2024Article
- Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer.Journal of cellular and molecular medicine · 2024Article
- Causal relationships between gut microbiota, immune cell, and Henoch-Schönlein Purpura: a two-step, two-sample Mendelian randomization study.Frontiers in immunology · 2024Article
- Regulatory T cells in dominant immunologic tolerance.The Journal of allergy and clinical immunology · 2024Review
- Susceptibility of SARS-CoV2 infection in children.European journal of pediatrics · 2023Review
- Kawasaki Disease and Multisystem Inflammatory Syndrome in Children: Common Inflammatory Pathways of Two Distinct Diseases.Rheumatic diseases clinics of North America · 2023Review
- Understanding COVID-19 in children: immune determinants and post-infection conditions.Pediatric research · 2023Review
- Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID.Vaccines · 2023Review
- Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children.The Journal of clinical investigation · 2023Article
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Authors and funding
51 authors at 16 institutions in 4 countries.
Mehdi BenamarDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Qian ChenDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Janet ChouDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Amélie M JuléDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Rafik BoudraBrigham and Women's Hospital, Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA.
Paola ContiniUnit of Clinical Immunology and Translational Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Elena CrestaniDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Peggy S LaiDivision of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA.
Muyun WangDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Jason FongDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Shira RockwitzThe Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, USA.
Pui LeeDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Tsz Man Fion ChanDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Ekin Zeynep AltunMinistry of Healthy, Marmara University Education and Training Hospital, Department of Pediatrics, Istanbul, Turkey.
Eda KepenekliMarmara University, Faculty of Medicine, Division of Pediatric Infectious Diseases, Istanbul, Turkey.
Elif Karakoc-AydinerDivision of Pediatric Allergy and Immunology, The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.
Ahmet OzenDivision of Pediatric Allergy and Immunology, The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.
Perran BoranMarmara University, Faculty of Medicine, Division of Social Pediatrics, Istanbul, Turkey.
Fatih AygunDivision of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Pinar OnalDivision of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Ayse Ayzit Kilinc SakalliDivision of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Haluk CokugrasDivision of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Metin Yusuf GelmezDepartment of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey.
Fatma Betul OktelikDepartment of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey.
Esin Aktas CetinDepartment of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey.
Yuelin ZhongDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Maria Lucia TaylorDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Katherine IrbyArkansas Children's Hospital, Little Rock, Arkansas, USA.
Natasha B HalasaDivision of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Elizabeth H MackDivision of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Overcoming COVID-19 Investigators
Sara SignaDINOGMI, Università degli Studi di Genova, Genova, Italy and Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Ignazia PrigioneCenter for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Marco GattornoCenter for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Nicola CotugnoClinical and Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Donato AmodioClinical and Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Raif S GehaDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Mary Beth SonDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Jane NewburgerDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Pankaj B AgrawalDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Stefano VolpiDINOGMI, Università degli Studi di Genova, Genova, Italy and Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Paolo PalmaClinical and Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Ayca KiykimDivision of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Adrienne G RandolphDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Gunnur DenizDepartment of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey.
Safa BarisDivision of Pediatric Allergy and Immunology, The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.
Raffaele De PalmaUnit of Clinical Immunology and Translational Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Klaus Schmitz-AbeDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Louis-Marie CharbonnierDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Lauren A HendersonDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Talal A ChatilaDivision of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
Boston Children's Hospital · USIstanbul University-Cerrahpaşa · TRIstanbul University · TRIstituto Giannina Gaslini · ITCenter for Translational Molecular Medicine · NLMarmara University · TRUniversity of Rome Tor Vergata · ITArkansas Children's Hospital · USBambino Gesù Children's Hospital · ITBoston Children's Museum · USBrigham and Women's Hospital · USHarvard University · USInstitute of Applied Science and Intelligent Systems · ITMedical University of South Carolina · USMinistry of Health · TRVanderbilt University Medical Center · US
Funding
Molecular Basis of Hyper lgE ImmunodeficiencyR01AI065617 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Talal Amine Chatila · 2006 to 2026
$10.9MJoint Biology Consortium Resource-based CenterP30AR070253 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Peter A Nigrovic, Jeffrey Andrew Sparks · 2016 to 2026
$9.4MMechanisms of a Novel Combined Immunodeficiency Caused by a Homozygous Mutation in COPG1R01AI139633 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI GEHA, RAIF SALIM · 2018 to 2022
$3.1MControl of regulatory T cell homeostasis and function by Notch signalingR01AI115699 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI CHATILA, TALAL AMINE · 2017 to 2021
$2.2MMechanisms of pediatric overweight and obesity underlying susceptibility to multisystem inflammatory syndrome in children (MIS-C)R01DK130465 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI CHOU, JANET · 2021 to 2023
$1.4MThe Reprogramming of Regulatory T cells to a Th17 Phenotype in Systemic Juvenile Idiopathic ArthritisK08AR073339 · NIAMS · BOSTON CHILDREN'S HOSPITAL · PI HENDERSON, LAUREN A · 2018 to 2022
$840kControl of regulatory T cell homeostasis and function by Notch signalingR56AI115699 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI CHATILA, TALAL AMINE · 2015 to 2015
$442kNIAID NIH HHS R01 AI065617NIAID NIH HHS R01 AI115699NIAID NIH HHS R01 AI139633NIAID NIH HHS R56 AI115699NIAMS NIH HHS K08 AR073339NIAMS NIH HHS P30 AR070253NIDDK NIH HHS R01 DK130465
Abstract
Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
Indexed as
COVID-19SARS-CoV-2ChildHumansInflammationReceptor, Notch1Sialic Acid Binding Ig-like Lectin 2Systemic Inflammatory Response SyndromeT-Lymphocytes, RegulatoryCD22 protein, humanNOTCH1 protein, humanReceptor, Notch1Sialic Acid Binding Ig-like Lectin 2Adaptive immunityCOVID-19ImmunologyT cellsTolerance
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