Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

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.

Keywords: T-follicular regulatory cell; cell therapy; immunosuppression; regulatory T cell; transplantation.

Figure 1

Early germinal center reaction and T follicular regulatory cell maturation process. Early Tfr (eTfr) derive from natural regulatory T cells (Tregs) after expression of CXCR5 and Bcl-6 and down regulation of FOXP3. After interaction with activated dendritic cells (DC) in the T cell zone, some eTfr lose expression of Bcl-6 and enter the circulation (blood Tfr-bTfr), while some migrate to the follicle (intermediate Tfr-iTfr), where they interact with the follicular B cells and start expressing PD-1 and ICOS. Eventually, they move to the germinal center (GC), becoming mature Tfr (mTfr), where they inhibit both the central T follicular helper cell (cTfh) and the GC B cells, leading to regulation of antibody production and B cell differentiation.

Figure 2

Different Tregs Good Manufacturing Product (GMP)-compatible expansion protocols and potential areas to improve for Tfr cell therapy. In the top diagram are described some of the protocols in use in our GMP facility (126, 127, 135) for the expansion of Tregs from the isolation step (using either magnetic beads or cell sorting) to the other steps such as stimulation every 12 days (with anti-CD3/CD28 beads) and feeding every 48 h. The use of IL-2 and rapamycin has been shown necessary to expand functional and stable Tregs in the absence of T effectors. In the bottom diagram is described a similar process for the generation of a Tfr product and in red are all the different steps which remains to be optimized.