Superantigenic TCR Vbeta 21.3 signature in Multisystem Inflammatory Syndrome in Children

Moreews, M.; Le Gouge, K.; Bellomo, A.; Malcus, C.; Pescarmona, R.; Khaldi-Plassart, S.; Djebali, S.; Mathieu, A.-L.; Perret, M.; Villard, M.; Chopin, E.; Rouvet, I.; Vandenesh, F.; Dupieux, C.; Pouyau, R.; Teyssedre, S.; Guerder, M.; Louazon, T.; Anne-Moulin-Zinsch,; Duperril, M.; Patural, H.; Giovannini-Chami, L.; Portefaix, A.; Kassai, B.; Venet, F.; Monneret, G.; Lombard, C.; Flodrops, H.; Bastard, P.; Zhang, S.-Y.; Dubois, V.; Thaunat, O.; Richard, J.-C.; Mezidi, M.; Abel, L.; Casanova, J. L.; Marvel, J.; Trouillet-Assant, S.; Klatzmann, D.; Walzer, T.; Dreux, M.; Mariotti-Ferrandiz, E.

ObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS). MethodsChildren with suspected MIS-C were included within the first week of diagnosis and a large scale immunoassay was performed to determein the immunologic signature of these patients. ResultsWe characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the V{beta}21.3 T cell receptor {beta} chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and V{beta}21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the V{beta} 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation. ConclusionsOur findings argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal V{beta}21.3 T cell expansion. Key messagesWhat is already known about this subject ? MIS-C occurs 3-5 weeks after acute SARS-CoV2 infection and overlap features of Toxic Shock syndrome and Kawasaki disease. MIS-C appears different in term of cytokine and autoantibodies generation from KD with subtle signs of T cells activation What does this study add? This study demonstrates that V{beta}21.3+ CD4 and CD8 T cells are highly increased in about 50% of MIS-C and distinctive of the V{beta}2+ expansion observed in toxic shock syndrome in This reflects a specific T cell activation and cytokine release syndrome similar to toxic shock syndrome How mich this impact on clinical practice or future developments? V{beta}21.3+ signature can be available on a short term basis by flowcytometry and represents a signature of the MIS-C. As for TSS, immunomodulating therapies may revert the superantigenic activation and resolve this life threatening pediatric condition.