Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation.

Background: Although antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood.

Methods: Using high-dimensional flow cytometry, assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (T) cells and B cells during ABMR in 105 kidney transplant recipients.

Results: There were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients. We identified proliferating populations of circulating T cells and activated B cells emerging in blood of patients undergoing ABMR. Although these circulating T cells comprised heterogeneous phenotypes, they were dominated by activated (ICOSPD-1) and early memory precursor (CCR7CD127) subsets, and were enriched for the transcription factors IRF4 and c-Maf. These circulating T cells produced large amounts of IL-21 upon stimulation with donor antigen and induced B cells to differentiate into antibody-secreting cells that produced DSAs. Combined analysis of the matched circulating T cell and activated B cell RNA-sequencing profiles identified highly coordinated transcriptional programs in circulating T cells and B cells among patients with ABMR, which markedly differed from those of patients who did not develop DSAs or ABMR. The timing of expansion of the distinctive circulating T cells and activated B cells paralleled emergence of DSAs in blood, and their magnitude was predictive of IgG3 DSA generation, more severe allograft injury, and higher rate of allograft loss.

Conclusions: Patients undergoing ABMR may benefit from monitoring and therapeutic targeting of T cell-B cell interactions.