Receptor-tethered orthogonal IL-2 enhances regulatory T cell therapy.

Authors

Alyssa C Indart, Huiyun Lyu, Vinh Q Nguyen, Wendy Rosenthal, Jatin R Palvai, Sophie S Jang, Yue Chen, Kevin Jude, Leon Su, K Christopher Garcia, Jeffrey A Bluestone, Qizhi Tang

Published in

The Journal of experimental medicine. Volume 223. Issue 9. Sep 07, 2026. Epub Aug 12, 2026.

Abstract

Regulatory T cell (Treg) therapy is an emerging platform for controlling immune overactivation. Persistence of infused Tregs is limited by insufficient IL-2, which is essential for Treg survival and function. IL-2 activates many immune cells, imposing a challenge for the selective provision of IL-2 to infused Tregs. In this study, we found that infusions of orthogonal (ortho) IL-2 failed to enhance Tregs expressing a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. Engineering Tregs with an orthoIL-2 tethered to its receptor achieved selective autocrine signaling; increased CD25, CTLA-4, and Foxp3 expression; supported Treg persistence without exogenous IL-2 in vivo; and improved the efficacy of Treg prevention of autoimmune diabetes. Inserting the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific self-reinforced expression through the activation of the Foxp3 locus by increased IL-2 signaling. Together, these results illustrate a safe and effective cell-engineering solution for overcoming Tregs' dependency on exogenous IL-2, thereby achieving superior therapeutic efficacy.

PMID:
42584417
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.