Charmetant, XavierXavierCharmetantCHIEN-CHIA CHENHamada, SarahSarahHamadaGoncalves, DavidDavidGoncalvesSaison, CaroleCaroleSaisonRabeyrin, MaudMaudRabeyrinet al.,et al.2023-02-222023-02-222022-09-211946-6234https://scholars.lib.ntu.edu.tw/handle/123456789/628655The 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.enMEDIATED REJECTIONHLA ANTIBODIESMONOCLONAL-ANTIBODYCELLULAR REJECTIONT-CELLSALLOGRAFTPATHWAYALLOANTIBODYLUNGENGAGEMENTjournal article10.1126/scitranslmed.abg1046361300132-s2.0-85138234579WOS:000869432500004