期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 8, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI139991
关键词
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资金
- NIH [P01 HL075462, UC4DK116264, R01 HL11879, NIAID R37 34495, K08 HL151809, SIG S10RR027431-01]
- Howard Hughes Medical Institute
- Parker Institute for Cancer Immunotherapy
- Japan Society for the Promotion of Science (JSPS) (KAKENHI) [15KK0355]
- Geneva University Hospitals Fellowship
- Swiss Cancer League [BIL KLS 3806-02-2016]
- Fondation de Bienfaisance Valeria Rossi di Montelera (Eugenio Litta Fellowship)
- Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI)
- St. Baldrick's Foundation Scholar Award
- Grants-in-Aid for Scientific Research [15KK0355] Funding Source: KAKEN
The study demonstrates an innovative approach to enhance the expansion and target cell stimulation ability of Treg cells through engineered orthogonal IL-2/IL-2R pair, which improves the potential for organ transplantation tolerance.
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.
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