Abstract
Regulatory T cells (Tregs) constitute a small proportion of circulating CD4+ T cells that function to maintain homeostasis and prevent autoimmunity. In light of their powerful immunosuppressive and tolerance-promoting properties, Tregs have become an interesting potential candidate for therapeutic use in conditions such as solid organ transplant or to treat autoimmune and inflammatory conditions. Clinical studies have demonstrated the safety of polyclonally expanded Tregs in graft-versus-host disease, type 1 diabetes, and more recently in renal and liver transplantation. However, Tregs are heterogenous. Recent insights indicate that only a small proportion of Tregs, called T follicular regulatory cells (Tfr) regulate interactions between B cells and T follicular helper (Tfh) cells within the germinal center. Tfr have been mainly described in mouse models due to the challenges of sampling secondary lymphoid organs in humans. However, emerging human studies, characterize Tfr as being CD4+CD25+FOXP3+CXCR5+ cells with different levels of PD-1 and ICOS expression depending on their localization, in the blood or the germinal center. The exact role they play in transplantation remains to be elucidated. However, given the potential ability of these cells to modulate antibody responses to allo-antigens, there is great interest in exploring translational applications in situations where B cell responses need to be regulated. Here, we review the current knowledge of Tfr and the role they play focusing on human diseases and transplantation. We also discuss the potential future applications of Tfr therapy in transplantation and examine the evidence for a role of Tfr in antibody production, acute and chronic rejection and tertiary lymphoid organs. Furthermore, the potential impact of immunosuppression on Tfr will be explored. Based on preclinical research, we will analyse the rationale of Tfr therapy in solid organ transplantation and summarize the different challenges to be overcome before Tfr therapy can be implemented into clinical practice.
Highlights
Over the last three decades, despite an improvement in shortterm outcomes after solid organ transplantation, long-term outcomes have not drastically improved [1]
Immune mediated injury is the predominant cause of chronic allograft dysfunction (CAD), many cases of which are associated with the presence of donor specific antibodies (DSA), directed predominantly against donor human leukocyte antigens (HLA)
IL-2 is a key factor regulating T follicular regulatory cells (Tfr) differentiation, promoting Blimp1 expression while repressing Bcl6 in Tregs to preclude Tfr cell development [30]. They have been characterized as being CD4+ CD25+FOXP3+CXCR5+ cells with different levels of PD-1 and ICOS expression depending on their localization [31, 32] (and on the transcription factor Bcl-6 for differentiation and localization into the B cell follicle [4,5,6, 14, 33]
Summary
Over the last three decades, despite an improvement in shortterm outcomes after solid organ transplantation, long-term outcomes have not drastically improved [1]. Immune mediated injury is the predominant cause of CAD, many cases of which are associated with the presence of donor specific antibodies (DSA), directed predominantly against donor human leukocyte antigens (HLA) These DSA are produced by B cells in response to alloantigen stimulus through a process that is T-cell regulated [2]. Tfr have been extensively studied in mouse models, with fewer studies in humans, due to the challenges of sampling human SLO In human, they have been characterized as being Tfh-like [expressing CD4, the C-X-C chemokine receptor type 5 (CXCR5) and Bcl-6 in association with CD25 and FOXP3] and express varying levels of PD-1 and ICOS depending on their localization.
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