TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
Levi Hoste, Lisa Roels, Leslie Naesens, Victor Bosteels, Stijn Vanhee, Sam Dupont, Cedric Bosteels, Robin Browaeys, Niels Vandamme, Kevin Verstaen, Jana Roels, Karel F A Van Damme, Bastiaan Maes, Elisabeth De Leeuw, Jozefien Declercq, Helena Aegerter, Leen Seys, Ursula Smole, Sofie De Prijck, Manon Vanheerswynghels, Karlien Claes, Veronique Debacker, Gert Van Isterdael, Lynn Backers, Kathleen B M Claes, Paul Bastard, Emmanuelle Jouanguy, Shen-Ying Zhang, Gilles Mets, Joke Dehoorne, Kristof Vandekerckhove, Petra Schelstraete, Jef Willems, MIS-C Clinicians, Patrick Stordeur, Sophie Janssens, Rudi Beyaert, Yvan Saeys, Jean-Laurent Casanova, Bart N Lambrecht, Filomeen Haerynck, Simon J Tavernier
Author Information
Levi Hoste: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
Lisa Roels: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
Leslie Naesens: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
Victor Bosteels: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Stijn Vanhee: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Sam Dupont: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Cedric Bosteels: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Robin Browaeys: Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. ORCID
Niels Vandamme: Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. ORCID
Kevin Verstaen: Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. ORCID
Jana Roels: Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. ORCID
Karel F A Van Damme: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Bastiaan Maes: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Elisabeth De Leeuw: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Jozefien Declercq: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Helena Aegerter: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Leen Seys: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Ursula Smole: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Sofie De Prijck: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Manon Vanheerswynghels: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Karlien Claes: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
Veronique Debacker: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
Gert Van Isterdael: VIB Flow Core, VIB Center for Inflammation Research, Ghent, Belgium. ORCID
Lynn Backers: Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium. ORCID
Kathleen B M Claes: Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium. ORCID
Paul Bastard: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. ORCID
Emmanuelle Jouanguy: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. ORCID
Shen-Ying Zhang: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. ORCID
Gilles Mets: Department of Internal Medicine and Pediatrics, Division of Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium. ORCID
Joke Dehoorne: Department of Internal Medicine and Pediatrics, Division of Pediatric Rheumatology, Ghent University Hospital, Ghent, Belgium. ORCID
Kristof Vandekerckhove: Department of Internal Medicine and Pediatrics, Division of Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium. ORCID
Petra Schelstraete: Department of Internal Medicine and Pediatrics, Division of Pediatric Pulmonology, Infectious Diseases and Inborn Errors of Immunity, Ghent University Hospital, Ghent, Belgium. ORCID
Jef Willems: Department of Critical Care, Division of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium. ORCID
Patrick Stordeur: Belgian National Reference Center for the Complement System, Laboratory of Immunology, LHUB-ULB, Université Libre de Bruxelles, Brussels, Belgium. ORCID
Sophie Janssens: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Rudi Beyaert: Center for Inflammation Research, Laboratory of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium. ORCID
Yvan Saeys: Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium. ORCID
Jean-Laurent Casanova: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. ORCID
Bart N Lambrecht: Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium. ORCID
Filomeen Haerynck: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
Simon J Tavernier: Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium. ORCID
In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRβ repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.
References
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