Pretransplant circulating cTfh17 and donor-reactive T follicular helper responses distinguish liver transplant recipients who develop ischemia-reperfusion injury and donor-specific antibody

Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) is an early inflammatory event associated with alloreactive T cell activation and donor-specific antibody (DSA) production. How IRI promotes alloimmunity, especially the interplay between circulating T follicular helper (cTfh) cells and B cells and DSA development, remains poorly understood. We analyzed cTfh and B-cell subsets in 55 OLT recipients (IRI− = 28, IRI+ = 27) at preoperative, early posttransplantation (1-4 months), and late posttransplantation (6-12 months) time points to determine their relationship with DSA production. IRI+ patients exhibited significantly elevated pretransplant frequencies of circulating cTfh17 cells that persisted throughout early and late posttransplant periods. In functional assays, IRI+ patients also exhibited higher pre- and early posttransplant frequencies of alloreactive cTfh producing IL17A in response to donor stimulation. IRI+ patients were also associated with elevated frequencies of memory B cells (CD38−CD27+), switched memory B cells (SwM; CD38−CD27+IgD-) across all time points, along with a significant late posttransplantation increase in antibody-secreting B cells (ASCs; CD38+CD27+). Frequencies of PD-1+cTfh cells were positively correlated with ASC expansion and posttransplant DSA formation in IRI+ patients. Together, these findings demonstrate a previously unrecognized relationship between elevated pretransplant cTfh17 cells and donor-specific alloreactive cTfh responses in recipients who later developed IRI, accompanied by ASC expansion and DSA production after transplantation which may increase the risk of allograft rejection.