The suppressive effect on CD4 T-cell alloresponse against endothelial HLA-DR via PD-L1 induced by anti-A/B ligation.

While donor specific human leukocyte antigen (HLA) antibodies are a frequent cause for chronic antibody-mediated rejection in organ transplantation, this is not the case for antibodies targeting blood group antigens, as ABO-incompatible (ABO-I) organ transplantation has been associated with a favorable graft outcome. Here, we explored the role of CD4 T-cell-mediated alloresponses against endothelial HLA-DR in the presence of anti-HLA-class I or anti-A/B antibodies. CD4 T-cells, notably CD45RA-memory CD4 T-cells, undergo extensive proliferation in response to endothelial HLA-DR. The CD4 T-cell proliferative response was enhanced in the presence of anti-HLA-class I, but attenuated in the presence of anti-A/B antibodies. Microarray analysis and molecular profiling demonstrated that the expression of CD274 programmed death-ligand 1 (PD-L1) increased in response to anti-A/B ligation-mediated ERK inactivation in endothelial cells that were detected even in the presence of Interferon γ stimulation. Anti-PD-1 antibody enhanced CD4 T-cell proliferation, and blocked the suppressive effect of the anti-A/B antibodies. Educated CD25+CD127- regulatory T-cells (edu.Tregs) were more effective at preventing CD4 T-cell alloresponses to endothelial cells compared with naive Treg; anti-A/B antibodies were not involved in the Treg-mediated events. Finally, amplified expression of transcript encoding PD-L1 was observed in biopsy samples from ABO-I renal transplants when compared with those from ABO-identical/compatible transplants. Taken together, our findings identified a possible factor that might prevent graft rejection and thus contribute to a favorable outcome in ABO-I renal transplantation.