Inverted direct allorecognition triggers early donor-specific antibody responses after transplantation - Sorbonne Université Access content directly
Journal Articles Science Translational Medicine Year : 2022

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

Chien-Chia Chen
Sarah Hamada
  • Function : Author
Carole Saison
  • Function : Author
Virginie Mathias
  • Function : Author
Lara Chalabreysse
Lionel Couzi
Valérie Dubois

Abstract

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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Dates and versions

hal-04235839 , version 1 (12-10-2023)

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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⟩
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