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

Am J Transplant. 2022 Dec;22(12):3061-3068. doi: 10.1111/ajt.17181. Epub 2022 Sep 14.

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.

Keywords: animal models: murine; basic (laboratory) research/science; bioengineering; cellular biology; cytokines/cytokine receptors; immunobiology; immunosuppressant - calcineurin inhibitor (CNI); immunosuppression/immune modulation; tolerance: chimerism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin Inhibitors* / pharmacology
  • Graft Survival
  • Immunosuppressive Agents / therapeutic use
  • Interleukin-2 / metabolism
  • Mice
  • Receptors, Interleukin-2
  • T-Lymphocytes, Regulatory
  • Tacrolimus* / therapeutic use

Substances

  • Calcineurin Inhibitors
  • Tacrolimus
  • Interleukin-2
  • Receptors, Interleukin-2
  • Immunosuppressive Agents