Characterization of follicular T helper cells and donor-specific T helper cells in renal transplant patients with de novo donor-specific HLA-antibodies

Abstract

T follicular helper (T_FH) cells are a heterogeneous subset of immunocompetent T helper (T_H) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates T_FH cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (T_FR) cells counteract T_FH cell activity. Here, we investigated the implications of T_FH and T_FR cells on dnDSA formation after renal transplantation (RTX). Considering T_FH cells to be CXCR5⁺ and IL-21⁺, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive T_H cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in T_FH cells and an expanded reservoir of donor-specific memory T_H cells in patients with dnDSA. This warrants further investigations if aberrant T_FH cell activation may precede the formation of dnDSA promoting AMR.

Keywords: Allospecific T cell reactivity; Antibody-mediated rejection; Solid organ transplantation; T follicular helper cell; T follicular regulatory cell; de novo donor-specific HLA-antibodies.