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

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 B. Wagers, Melissa Mavers, Warren J. Leonard, Bruce R. Blazar, K. Christopher Garcia, Robert S. Negrin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere139991
JournalJournal of Clinical Investigation
Volume131
Issue number8
DOIs
StatePublished - Apr 15 2021

Bibliographical note

Funding Information:
This work was supported by grants from the NIH (P01 HL075462 to RSN, UC4DK116264 to KCG, R01 HL11879 and NIAID R37 34495 to BRB, K08 HL151809 to MM, and SIG S10RR027431-01 to Stanford Shared FACS Facility). We also acknowledge support from the Howard Hughes Medical Institute (to KCG, LKP, and LLS) and the Parker Institute for Cancer Immunotherapy (to KCG). TH has received grants from the Japan Society for the Promotion of Science (JSPS) (KAKENHI, Grants-in-Aid for Scientific Research) (15KK0355). Grants were also received from the Geneva University Hospitals Fellowship (to FS), the Swiss Cancer League (BIL KLS 3806-02-2016 to FS), and the Fondation de Bienfaisance Valeria Rossi di Montelera (Eugenio Litta Fellowship to FS). JXL, PL, and WJL were supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI). Next-generation sequencing for the RNA-Seq samples was performed in the NHLBI DNA Sequencing Core. MM received the St. Baldrick's Foundation Scholar Award.

Funding Information:
This work was supported by grants from the NIH (P01 HL075462 to RSN, UC4DK116264 to KCG, R01 HL11879 and NIAID R37 34495 to BRB, K08 HL151809 to MM, and SIG S10RR027431-01 to Stanford Shared FACS Facility). We also acknowledge support from the Howard Hughes Medical Institute (to KCG, LKP, and LLS) and the Parker Institute for Cancer Immunotherapy (to KCG). TH has received grants from the Japan Society for the Promotion of Science (JSPS) (KAKENHI, Grants-in-Aid for Scien- tific Research) (15KK0355). Grants were also received from the Geneva University Hospitals Fellowship (to FS), the Swiss Cancer League (BIL KLS 3806-02-2016 to FS), and the Fondation de Bienfaisance Valeria Rossi di Montelera (Eugenio Litta Fellowship to FS). JXL, PL, and WJL were supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHL-BI). Next-generation sequencing for the RNA-Seq samples was performed in the NHLBI DNA Sequencing Core. MM received the St. Baldrick’s Foundation Scholar Award.

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

PubMed: MeSH publication types

  • Journal Article

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