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

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.

Passenger donor lymphocytes: To affinity and beyond

“…Such responses would be expected to contribute to graft rejection. To that end, Charmetant and colleagues report intragraft microvascular lesions associated with donor T cell--mediated alloantibody production (1). Similarly, in our murine model of chronic antibodymediated rejection, allograft vasculopathy was diminished, and heart graft survival prolonged, when donor hearts were first depleted of T cells (3).…”

“…Rather, concurrent signaling through the B cell receptor (BCR) is essential for antibody production. Charmetant and colleagues now demonstrate that increased B cell proliferation and upregulation of MHC II occurred if B cells were co-cultured with third -party T cells, but only if the BCR was simultaneously cross-linked (1). Similarly, we previously reported that adoptively-transferred third -party CD4 + T cells could provide help in T cell--deficient mice for antibody responses against a model antigen, but only if simultaneously challenged with that antigen (3).…”

“…These CD4 + T cells are thought to recognize processed target alloantigen presented as peptide fragments complexed to the MHC II complex of a B cell. However, in this issue of Science Translational Medicine, Charmetant et al (1) have outlined an unexpected pathway for donor -specific alloantibody production, which the authors term an "inverted" direct response. The authors found, using a murine cardiac allograft model, that recipient B cells were instead activated as a consequence of help provided by donor CD4 + T cells that were passengers within the allograft.…”

Single-Cell Heterogeneity Restorative Chimeric Engineering Nanoparticles for Alleviating Antibody-Mediated Allograft Injury

“…The disorder of single-cell transcriptional heterogeneity is an inevitable outcome of persistent allosensitive responses after transplantation. − Alloantigens are rapidly drained into the secondary lymphoid tissue once the graft is implanted to the recipient, activating an adaptive immune response . Afterward, donor-specific antibodies (DSAs) are produced and bound to the antigens exposed on the surface of vascular endothelial cells, activating the complement system or directly leading to endothelial cell apoptosis and detachment through cytotoxicity .…”

“…1−3 Alloantigens are rapidly drained into the secondary lymphoid tissue once the graft is implanted to the recipient, activating an adaptive immune response. 4 Afterward, donor-specific antibodies (DSAs) are produced and bound to the antigens exposed on the surface of vascular endothelial cells, activating the complement system or directly leading to endothelial cell apoptosis and detachment through cytotoxicity. 5 Endothelial cell injury not only causes the proliferation and activation of alloreactive immune cells but also promotes the infiltration of inflammatory cells, including neutrophils, monocytes, and lymphocytes, thus leading to multitype and multidimensional single-cell transcriptional disorders.…”