Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance
Toshihito Hirai, … , K. Christopher Garcia, Robert S. Negrin
Toshihito Hirai, … , K. Christopher Garcia, Robert S. Negrin
Published April 15, 2021
Citation Information: J Clin Invest. 2021;131(8):e139991. https://doi.org/10.1172/JCI139991.
View: Text | PDF
Research Article

Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance

Abstract

Adoptive transfer of Tregs has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrate an innovative approach to engineering an orthogonal IL-2/IL-2 receptor (IL-2R) pair, the parts of which selectively interact with each other, transmitting native IL-2 signals, but do not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed hematopoietic chimerism model, orthogonal IL-2 injection significantly promoted orthogonal IL-2R+Foxp3GFP+CD4+ cell proliferation without increasing other T cell subsets and facilitated donor hematopoietic cell engraftment followed by acceptance of heart allografts. Our data indicate that selective target cell stimulation enabled by the engineered orthogonal cytokine receptor improves Treg potential for the induction of organ transplantation tolerance.

Authors

Toshihito Hirai, Teresa L. Ramos, Po-Yu Lin, Federico Simonetta, Leon L. Su, Lora K. Picton, Jeanette Baker, Jian-Xin Lin, Peng Li, Kinya Seo, Juliane K. Lohmeyer, Sara Bolivar-Wagers, Melissa Mavers, Warren J. Leonard, Bruce R. Blazar, K. Christopher Garcia, Robert S. Negrin

×

Figure 6

Ortho IL-2 treatment facilitates donor-specific heart transplantation tolerance.

Options: View larger image (or click on image) Download as PowerPoint
Ortho IL-2 treatment facilitates donor-specific heart transplantation to...
Recipients of H2b+ BMT received heart allografts from luc+H2b+ or luc+H2q+ donor mice 2 months after BMT. (A) Representative bioluminescent images show acceptance or rejection of heart allografts in the mice that developed mixed chimerism (chimeric recipient) and in the mice that rejected H2b+ BMCs (nonchimeric recipient). Survival curve for H2b+ heart allograft (B) and H2q+ heart allografts (C) are shown. P values calculated by log-rank test between indicated 2 groups. (D and E) Recipient mice that received oTregs were sacrificed 30 days after H2q+ heart transplantation. Negatively isolated T cells were cocultured with host type (H2d+), third-party type (H2q+), and BM donor type (H2b+) stimulator cells, and the percentage of proliferating cells was analyzed by flow cytometry on d4. (D) Representative pseudocolor plots showing dilution of proliferation dye. SSC, side scatter. (E) Box plots for percentages of proliferating cells. Dunn’s Kruskal-Wallis multiple comparisons calculated among the 3 treatment groups. Pooled data from 2 independent experiments, including 5 mice per group per experiment. *P < 0.05; ***P < 0.001.