Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

Marion Moreews (1) , Kenz Le Gouge (2) , Samira Khaldi-Plassart (3, 4) , Rémi Pescarmona (1, 4, 3, 5) , Anne-Laure Mathieu (1) , Christophe Malcus (3, 6, 7) , Sophia Djebali (1) , Alicia Bellomo (1) , Olivier Dauwalder (1, 8, 3) , Magali Perret (1, 3, 5) , Marine Villard (1, 3, 5) , Emilie Chopin (3) , Isabelle Rouvet (3) , Francois Vandenesch (1, 8, 3) , Céline Dupieux (1, 8, 3) , Robin Pouyau (3) , Sonia Teyssedre (3) , Margaux Guerder (3) , Tiphaine Louazon (9) , Anne Moulin-Zinsch (10, 3) , Marie Duperril (11) , Hugues Patural (12, 11) , Lisa Giovannini-Chami (13, 14) , Aurélie Portefaix (15) , Behrouz Kassai (15) , Fabienne Venet (1, 3, 6) , Guillaume Monneret (3, 6, 7) , Christine Lombard (3, 5) , Hugues Flodrops (16) , Jean-Marie de Guillebon (13) , Fanny Bajolle (17) , Valérie Launay (3) , Paul Bastard (18) , Shen-Ying Zhang (18, 19) , Valérie Dubois (20) , Olivier Thaunat (1, 20, 6, 21) , Jean-Christophe Richard (22, 3, 23, 24, 25) , Mehdi Mezidi (22, 3, 23) , Omran Allatif (1) , Kahina Saker (1, 3) , Marlène Dreux (1) , Laurent Abel (18, 19) , Jean-Laurent Casanova (18, 19, 26) , Jacqueline Marvel (1) , Sophie Trouillet-Assant (1, 3) , David Klatzmann (27, 28) , Thierry Walzer (1) , Encarnita Mariotti-Ferrandiz (28, 2) , Etienne Javouhey (7, 3) , Alexandre Belot (1, 3, 6)

1 CIRI - Centre International de Recherche en Infectiologie
2 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
3 HCL - Hospices Civils de Lyon
4 RAISE - Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon]
5 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
6 Hôpital Edouard Herriot [CHU - HCL]
7 PI3 - Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression
8 Centre National de Reference des Staphylocoques
9 Centre hospitalier de Valence
10 Hôpital Louis Pradel [CHU - HCL]
11 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
12 SAINBIOSE - Santé Ingénierie Biologie Saint-Etienne
13 CHU-Lenval - Hôpitaux Pédiatriques de Nice Lenval
14 UniCA - Université Côte d'Azur
15 CIC CHU Lyon (inserm)
16 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
17 Hôpital Necker - Enfants Malades [AP-HP]
18 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
19 Rockefeller University [New York]
20 EFS - Etablissement français du sang - Auvergne-Rhône-Alpes
21 UCBL - Université Claude Bernard Lyon 1
22 Hôpital de la Croix-Rousse [CHU - HCL]
23 Université de Lyon
24 CREATIS - Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé
25 MYRIAD - Modeling & analysis for medical imaging and Diagnosis
26 HHMI - Howard Hughes Medical Institute [Boston]
27 ESA - Equipe de Statistique Appliquée (UMRS 1158)
28 CHU Pitié-Salpêtrière [AP-HP]

Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.

Mots clés: MIS-C; PIMS; COVID-19; SARS-CoV2; post-infectious disease; Kawasaki disease; Toxic Shock Syndrome; Immune profiling; TCR sequencing; myocarditis

Domaines: Immunité adaptative; Maladies émergentes; Maladies infectieuses; Pédiatrie

Marion Moreews, Kenz Le Gouge, Samira Khaldi-Plassart, Rémi Pescarmona, Anne-Laure Mathieu, et al.. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children. Science Immunology, 2021, 6 (59), pp.eabh1516. ⟨10.1126/sciimmunol.abh1516⟩. ⟨hal-03298662⟩