Inverted direct allorecognition triggers early donor-specific antibody responses after transplantation

Xavier Charmetant (1) , Chien-Chia Chen , Sarah Hamada , David Goncalves (1) , Carole Saison , Maud Rabeyrin (2) , Marion Rabant (3) , Jean-Paul Duong van Huyen (3) , Alice Koenig (1, 4) , Virginie Mathias , Thomas Barba (1) , Florence Lacaille (5) , Jérôme Le Pavec (6, 7) , Olivier Brugière (8) , Jean-Luc Taupin (9, 10) , Lara Chalabreysse (2) , Jean-François Mornex (11, 2) , Lionel Couzi (12) , Stéphanie Graff-Dubois (13) , Raphaël Jeger-Madiot (13) , Alexy Tran-Dinh (14) , Pierre Mordant (15) , Helena Paidassi (1) , Thierry Defrance (1) , Emmanuel Morelon (1, 4) , Lionel Badet (4) , Antonino Nicoletti (14) , Valérie Dubois , Olivier Thaunat (1, 4)

1 CIRI - Centre International de Recherche en Infectiologie
2 GHE - Groupement Hospitalier Lyon-Est
3 Département de Pathologie [CHU Necker]
4 Hôpital Edouard Herriot [CHU - HCL]
5 CHU Necker - Enfants Malades [AP-HP] - Gastro-Entérologie, Hépatologie et Nutrition pédiatriques
6 Hôpital Marie-Lannelongue
7 HPPIT - Hypertension pulmonaire : physiopathologie et innovation thérapeutique
8 Hôpital Foch [Suresnes]
9 HIPI (UMR_S_976 / U976) - Immunologie humaine, physiopathologie & immunothérapie
10 AP-HP - Hopital Saint-Louis [AP-HP]
11 IVPC - Infections Virales et Pathologie Comparée - UMR 754
12 Hôpital Pellegrin
13 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
14 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
15 Service de Chirurgie Thoracique et Vasculaire [Hôpital Bichat]

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.

Domaines: Sciences du Vivant [q-bio]

Xavier Charmetant, Chien-Chia Chen, Sarah Hamada, David Goncalves, Carole Saison, et al.. Inverted direct allorecognition triggers early donor-specific antibody responses after transplantation. Science Translational Medicine, 2022, 14 (663), ⟨10.1126/scitranslmed.abg1046⟩. ⟨hal-04235839⟩