Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies

Abstract

Regulatory T cells (Tregs) are CD4⁺ T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy.

Keywords: graft-versus-host disease; immunotherapy; regulatory T cells; rejection; suppression; transplant.

Figure 1

Strategy behind Treg therapies in solid organ and hematopoietic cell transplantation. Shown are the strategies associated with using Tregs in solid organ (left hand side) and hematopoietic cell transplantation (HCT) (right-hand side). Solid organ transplant; transplanted tissue [red HLA antigen (Ag) with green tissue antigens] are rejected by recipient conventional T cells (Tcons) recognizing donor APC/Ag (red). Only a proportion of the donor T cells will react to the donor antigen-presenting cells (APCs) (10–20% alloreactive T cells shaded in red). Recipient or third-party Tregs are isolated pretransplant with six strategy types; Unmanipulated Tregs are small in number and only a small proportion will be allo-reactive (shaded in red). This proportion is unknown but is likely to be in the same order as the proportion of alloreactive Tcons. Polyclonal expanded Tregs are larger in numbers but the same proportion of alloreactive Tregs (red shaded). Alloexpanded Tregs are expanded to donor APCs and while the resulting product will have a smaller cell number than polyclonal expansion there will be a higher proportion of donor reactive Tregs (red shaded). Chimeric antigen receptor (CAR) Tregs are recipient Tregs modified to recognize tissue antigen (green). Third-party Tregs, expanded are polyclonal expanded third-party Tregs that rely on the alloreactivity of the Treg population. As these are third party, this proportion maybe different to the recipient Treg populations and they may react to both donor and recipient (red and blue shaded Tregs). Third-party and Ag expanded Tregs are third-party Tregs (adult or cord) expanded to a third-party antigen (orange) not present in either the recipient or the donor. The third-party antigen can be supplied (either as APC or antigen) to the recipient and suppression of the rejection event is through bystander suppression. Withdrawing the antigen should then reduce the activation of the Tregs. HCT; Recipient (R) T cells (red shaded) respond to in coming donor (D) APCs (red) for a recipient vs. donor graft-versus-host disease (GvHD). Donor T cells (blue shaded) react to recipient APCs (blue) for a donor vs. recipient GvHD reaction. The levels of recipient cells will depend on the level of preconditioning (MAC or RIC) and the amount of mismatch. Treg therapy; Donor or third-party Treg are harvested. Unmanipulated Tregs; as with solid organ but target is now recipient antigens. Polyclonal expanded Tregs; as solid organ. Alloexpanded Tregs; donor Tregs expanded to recipient APCs. CAR Tregs; as solid organ but unique recipient Ag third-party allo Tregs; as with solid organ. Third-party Tregs expanded: as with solid organ.