IL-2 receptor engineering enhances regulatory T cell function suppressed by calcineurin inhibitor

Abstract

Clinical trials utilizing regulatory T cell (Treg) therapy in organ transplantation have shown promising results, however, the choice of a standard immunosuppressive regimen is still controversial. Calcineurin inhibitors (CNIs) are one of the most common immunosuppressants for organ transplantation, although they may negatively affect Tregs by inhibiting IL‐2 production by conventional T cells. As a strategy to replace IL‐2 signaling selectively in Tregs, we have introduced an engineered orthogonal IL‐2 (ortho IL‐2) cytokine/cytokine receptor (R) pair that specifically binds with each other but does not bind with their wild‐type counterparts. Murine Tregs were isolated from recipients and retrovirally transduced with ortho IL‐2Rβ during ex vivo expansion. Transduced Tregs (ortho Tregs) were transferred into recipient mice in a mixed hematopoietic chimerism model with tacrolimus administration. Ortho IL‐2 treatment significantly increased the ortho IL‐2Rβ(+) Treg population in the presence of tacrolimus without stimulating other T cell subsets. All the mice treated with tacrolimus plus ortho IL‐2 achieved heart allograft tolerance, even after tacrolimus cessation, whereas those receiving tacrolimus treatment alone did not. These data demonstrate that Treg therapy can be adopted into a CNI‐based regimen by utilizing cytokine receptor engineering.

Eras of designer Tregs: Harnessing synthetic biology for immune suppression

“…An alternative approach is to utilize an orthogonal receptor‐ligand system, in which an exogenously administered IL‐2 mutein selectively binds an orthogonal receptor expressed on T cells 148 . Tregs expressing this orthogonal IL‐2 receptor have demonstrated enhanced proliferation and survival in vivo, leading to improved heart allograft survival, when the ligand was simultaneously administered 149 . Other more complex strategies have also been developed, including artificial receptors binding rapamycin and mediating downstream IL‐2 signaling 150 and Tregs coated with redox‐sensitive IL‐2 nanogels that release IL‐2 upon TCR stimulation 151 .…”

“…A2‐CAR Tregs expressing a membrane‐bound IL‐2 were better able to survive and function compared to standard A2‐CAR Tregs when coadministered with multiple injections of tacrolimus 147 . Similarly, an orthogonal IL‐2 system enhanced the survival and proliferation of Tregs in mice treated with tacrolimus and helped maintain heart allograft tolerance 149 . Therefore, Treg engineering can be used to overcome the negative effects of immunosuppressive drugs.…”

“…148 Tregs expressing this orthogonal IL-2 receptor have demonstrated enhanced proliferation and survival in vivo, leading to improved heart allograft survival, when the ligand was simultaneously administered. 149 Other more complex strategies have also been developed, including artificial receptors binding rapamycin and mediating downstream IL-2 signaling 150 and Tregs coated with redox-sensitive IL-2 nanogels that release IL-2 upon TCR stimulation. 151 However, the effect of continuous IL-2 signaling on Tregs is still uncharted territory.…”

“…147 Similarly, an orthogonal IL-2 system enhanced the survival and proliferation of Tregs in mice treated with tacrolimus and helped maintain heart allograft tolerance. 149 Therefore, Treg engineering can be used to overcome the negative effects of immunosuppressive drugs.…”

Combining Treg Therapy With Donor Bone Marrow Transplantation: Experimental Progress and Clinical Perspective

“…82 The Negrin group recently developed Treg transduced with orthogonal IL-2/IL-2 receptors. 83,84 Treatment with orthogonal IL-2 solely activates and expands Treg bearing the respective orthogonal receptor, without influencing other T-cell subtypes. Employing this orthogonal system improved donor BM engraftment and increased survival of cardiac allografts.…”