T Follicular Regulatory Cells and Antibody Responses in Transplantation

Abstract

De novo donor-specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitization, limiting future transplant options. Forming high-affinity, long-lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. T follicular regulatory cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses.An imbalance between helper function and regulatory function can lead to excessive antibody production. High proportions of Tfh cells have been associated with DSA formation in transplantation; therefore, Tfr cells are likely to play an important role in limiting DSA production. Understanding the signals that govern Tfr cell development and the balance between helper and regulatory function within the GC is key to understanding how these cells might be manipulated to reduce the risk of DSA development.This review discusses the development and function of Tfr cells and their relevance to transplantation. In particular how current and future immunosuppressive strategies might allow us to skew the ratio between Tfr and Tfh cells to increase or decrease the risk of de novo DSA formation.

Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation

“…In addition, Foxp3 acts as a marker for regulatory T cells (Tregs) and has a protective effect on infiltration in immune organs. Foxp3+ T follicular regulatory cells (Tfrs) have recently been found to inhibit the onset of ABMR promoted by Tfh cells ( 47 , 48 ). The upregulation of splenic Foxp3 in the Allo+Combination group also revealed a possible alteration in regulatory T cell differentiation.…”

PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy

“…Tfr cells are believed to induce the inability of Tfh cells in the GC, specifically preventing incessant antibody-produced B cell responses. Subsequent evidence suggested that Tfr cells effectively regulated humoral immune responses in autoimmune diseases and organ transplantation 19,[56][57][58][59] . A leading theory is that Tfr cells are formidable adversaries against chronic graft-versus-host diseases (cGVHD) 59,60 .…”

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

“…The GC response is regulated by follicular regulatory T (Tfr) cells which are a subset of regulatory T cells (Tregs) [42,43]. Tfr cells share markers with both Tregs and Tfh cells [44,45] and recent studies suggest that they might perform their suppressive function not only inside the GC but also from the outside in [46]. Both pretransplant and dnDSA of the IgG class are strongly associated with acute and chronic allograft injury which suggests that GC reactions are crucial in the pathophysiology of ABMR in kidney transplant patients [47,48].…”