TIM3+<i> TRBV11-2</i> 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, Cédric Bosteels, Robin Browaeys, Niels Vandamme, Kevin Verstaen, Jana Roels, Karel 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 Claes, Paul Bastard, Emmanuelle Jouanguy, Shen‐Ying Zhang, Gilles Mets, Joke Dehoorne, Kristof Vandekerckhove, Petra Schelstraete, Jef Willems, Julie Willekens, Heidi Schaballie, Sabine Van daele, Laure Dierickx, Sara David, Evelyn Dhont, Ann Verrijckt, Annick De Jaeger, Emma Beel, Inge Matthijs, Aurélie Minne, Karin Decaestecker, J Murray John, Thomas E. M. Crijnen, Muriel Koninckx, Joery Verbruggen, Goele Nys, Samira Akhnikh, Koen Vanlede, Annelien Coppens, Joke Thijs, Ilse Ryckaert, Annick Covents, E Duval, Ann Verschelde, L. De Keyzer, T Van Ackere, Astrid Verbist, Charlotte Daeze, Caroline Becue, Justine De Paepe, Jo Keepers, Bruno Bruylants, Sabine Kuypers, Siel Daelemans, Jutte van der Werff ten Bosch, Gerlant van Berlaer, Alexandra Dreesman, Benoît Florkin, Cathérine Heijmans, Jean B. Papadopoulos, Patrick Stordeur, Sophie Janssens, Rudi Beyaert, Yvan Saeys, Jean‐Laurent Casanova, Bart N. Lambrecht, Filomeen Haerynck, Simon J. Tavernier
Abstract
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.