Pre-Transplant 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 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 pre-operative, early-post-transplantation (1-4 months), and late post-transplantation (6-12 months) timepoints to determine their relationship with DSA production. IRI+ patients exhibited significantly elevated pre-transplant frequencies of circulating cTfh17 cells that persisted throughout early and late post-transplant periods. In functional assays, IRI+ patients also exhibited higher pre- and early post-transplant frequencies of alloreactive cTfh producing IL17A in response to donor stimulation. IRI+ patients were also associated with elevated frequencies of memory B cells (MBCs; CD38-CD27+), switched memory B cells (SwM; CD38-CD27+IgD-) across all timepoints, along with a significant late post-transplantation increase in antibody-secreting B cells (ASCs; CD38+CD27+). Frequencies of PD-1+cTfh cells were positively correlated with ASC expansion and post-transplant DSA formation in IRI+ patients. Together, these findings demonstrate a previously unrecognized relationship between elevated pre-transplant 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 risk of allograft rejection.