Human Regulatory T Cells with Alloantigen Specificity Are More Potent Inhibitors of Alloimmune Skin Graft Damage than Polyclonal Regulatory T Cells

Alloantigen-specific human regulatory T cells may improve immunosuppressive therapy after transplantation. Slip Me Some Skin It’s never easy being the new kid on the block. You have to both look and act correctly to fit in. Skin grafts have similar problems—if they don’t express the same molecules as the surrounding host tissue, they will be rejected by the recipient’s own immune system. In the clinic, the standard way to combat this rejection is through the use of immunosuppressive drugs that broadly stem the immune response. However, general immune suppression has its own problems, including increased susceptibility to infection and cancer. In an ideal clinical scenario, only those immune cells responsible for attacking the transplant would be suppressed. Now, Sagoo et al. have established a way to do just that. Regulatory T cells (Tregs) can suppress specific types of immune activation; however, it is difficult to isolate Tregs restricted to particular antigens and then purify these cells in sufficient numbers to transfer into transplant recipients for targeted immune suppression. Sagoo et al. described a method to isolate such activated alloreactive Tregs, which specifically suppress effector immune cells that target antigens on donor tissue and cause rejection. These Tregs were sorted and expanded if they expressed two activation markers, CD69 and CD71, after allospecific activation in vitro. Transfer of these customized Tregs into a humanized mouse transplant model prevented transplant rejection and skin damage with higher efficacy than that associated with the transfer of nonspecific, polyclonal Tregs. This relatively simple isolation protocol should be translatable to the clinic and, thus, help skin transplants to “fit in. ” Graft rejection by the immune system is a major cause of transplant failure. Lifelong immunosuppression decreases the incidence of graft rejection; however, nonspecific immunosuppression results in increased susceptibly to infection and cancer. Regulatory T cells (Tregs), which suppress the activation of the immune system and induce tolerance, are currently under evaluation for use in clinical transplantation. Ex vivo expanded polyclonal Tregs that are introduced into transplant recipients alter the balance of T effector cells to Tregs; however, experimental data suggest that alloantigen-specific Tregs would be more effective at preventing graft rejection. We have developed a method to enrich alloantigen-specific human Tregs based on the coexpression of activation markers, CD69 and CD71. These Tregs could be readily expanded in vitro and demonstrated potent antigen-specific suppression. In a humanized mouse model of alloimmune-mediated injury of human skin grafts, alloantigen-specific Tregs resulted in a significant reduction in clinically relevant indicators of dermal tissue injury when compared with polyclonal Tregs, restoring a histology comparable to healthy skin. This method of human allospecific Treg selection should be scalable to the clinic. The improved in vivo efficacy of alloantigen-specific Tregs over polyclonal Tregs shown here suggests that generating “customized” Tregs with defined anti-donor allospecificities may improve current practice in clinical immunotherapy.