Contributors: Centre International de Recherche en Infectiologie (CIRI); École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Groupement Hospitalier Lyon-Est (GHE); Hospices Civils de Lyon (HCL); Département de Pathologie CHU Necker; Université Sorbonne Paris Cité (USPC)-Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité); Hôpital Edouard Herriot CHU - HCL; Gastro-Entérologie, Hépatologie et Nutrition pédiatriques (CHU Necker - Enfants Malades AP-HP ); Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Hôpital Marie-Lannelongue; Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay; Hôpital Foch Suresnes; Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Hopital Saint-Louis AP-HP (AP-HP); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Infections Virales et Pathologie Comparée - UMR 754 (IVPC); École Pratique des Hautes Études (EPHE); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Hôpital Pellegrin; CHU Bordeaux-Groupe hospitalier Pellegrin; Immunologie - Immunopathologie - Immunothérapie CHU Pitié Salpêtrière (I3); CHU Charles Foix AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU); Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord; Service de Chirurgie Thoracique et Vasculaire Hôpital Bichat; AP-HP - Hôpital Bichat - Claude Bernard Paris; ANR-10-IBHU-0004,OPeRa,Organ ProtEction and ReplAcement(2010); ANR-12-PDOC-0019,ESPRIT,Production d'allo-anticorps indépendante des LT CD4+ en transplantation: mécanistique et pistes thérapeutiques(2012); ANR-16-CE17-0007,PETTAR,Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe(2016)
نبذة مختصرة : International audience ; The generation of antibodies against donor-specific major histocompatibility complex (MHC) antigens, a type of donor-specific antibodies (DSAs), after transplantation requires that recipient’s allospecific B cells receive help from T cells. The current dogma holds that this help is exclusively provided by the recipient’s CD4 + T cells that recognize complexes of recipient’s MHC II molecules and peptides derived from donor-specific MHC alloantigens, a process called indirect allorecognition. Here, we demonstrated that, after allogeneic heart transplantation, CD3ε knockout recipient mice lacking T cells generate a rapid, transient wave of switched alloantibodies, predominantly directed against MHC I molecules. This is due to the presence of donor CD4 + T cells within the graft that recognize intact recipient’s MHC II molecules expressed by B cell receptor–activated allospecific B cells. Indirect evidence suggests that this inverted direct pathway is also operant in patients after transplantation. Resident memory donor CD4 + T cells were observed in perfusion liquids of human renal and lung grafts and acquired B cell helper functions upon in vitro stimulation. Furthermore, T follicular helper cells, specialized in helping B cells, were abundant in mucosa-associated lymphoid tissue of lung and intestinal grafts. In the latter, more graft-derived passenger T cells correlated with the detection of donor T cells in recipient’s circulation; this, in turn, was associated with an early transient anti–MHC I DSA response and worse transplantation outcomes. We conclude that this inverted direct allorecognition is a possible explanation for the early transient anti-MHC DSA responses frequently observed after lung or intestinal transplantations.
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