Circulating T Follicular Helper Cells Are a Biomarker of Humoral Alloreactivity and Predict Donor-Specific Antibody Formation After Transplantation.

Donor-specific antibodies (DSA) contribute to renal allograft loss. However, biomarkers to guide clinical management of DSA post-transplant or detect humoral alloimmune responses before alloantibodies develop are not available. Circulating T follicular helper (Tfh) cells are CD4+ CXCR5+ Tfh-like cells in the blood that have been associated with alloantibodies in transplant recipients, but whether they precede antibody formation for their evaluation as a predictive biomarker in transplantation is unknown. To evaluate the ability of circulating Tfh (cTfh) cells to predict DSA, we utilized murine transplant models to determine the temporal relationship between cTfh cells, germinal center (GC) formation, and DSA development. We observed that donor-reactive CD4+ CXCR5+ cTfh cells expand following allotransplantation. These cTfh cells were equivalent to graft-draining lymph node-derived Tfh cells in their ability to provide B cell help for antibody production. Circulating Tfh cell expansion and differentiation into ICOS+ PD-1+ cells temporally correlated with GC alloreactivity and preceded the generation of DSA in instances of modified and unmodified alloantibody formation. Importantly, delayed costimulation blockade initiated after the detection of ICOS+ PD-1+ cTfh cells prevented DSA. These findings suggest that cTfh cells could serve as a biomarker for humoral alloreactivity prior to the detection of alloantibodies and inform therapeutic approaches to prevent DSA. This article is protected by copyright. All rights reserved.