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

Toshihito Hirai, Po Yu Lin, Teresa L. Ramos, Federico Simonetta, Leon L. Su, Lora K. Picton, Jeanette Baker, Juliane K. Lohmeyer, K. Christopher Garcia, Robert S. Negrin*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
JournalAmerican Journal of Transplantation
Early online date28 Aug 2022
DOIs
Publication statusE-pub ahead of print - 28 Aug 2022
Externally publishedYes

Keywords

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

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