{"doi":"10.1101/2025.07.19.665688","title":"Receptor-tethered orthogonal IL-2 enhances regulatory T cell therapy","abstract":"Regulatory T cell (Treg) therapy is an emerging platform for controlling immune overactivation. Efficacy of Treg therapy is limited by the poor persistence of infused Tregs due to insufficient IL-2, which is essential for Treg survival and function. IL-2 activates many immune cells besides Tregs, imposing a challenge for the selective provision of IL-2 to infused Tregs. In this study, we found infusions of orthogonal (ortho) IL-2 failed to enhance Tregs engineered with a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. We then developed a receptor-tethered orthoIL-2 by optimizing the combination of IL-2, IL-2R, and the linker connecting them to achieve autocrine signaling selectively in engineered Tregs. Tregs expressing the tethered orthoIL-2 showed autocrine IL-2 signaling in vitro, enhanced CD25, CTLA-4, and Foxp3 expression, persisted without exogenous IL-2 in vivo, and prevented autoimmune diabetes using as few as 2,000 Tregs. Knocking the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific expression, with the additional benefit of positively reinforcing tethered orthoIL-2 expression through the activation of the Foxp3 gene by enhanced 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558572,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1459411,"name":"Huiyun Lyu","orcid":null,"position":1,"is_corresponding":false},{"id":246498,"name":"Vinh Nguyen","orcid":"0000-0003-2462-9594","position":2,"is_corresponding":false},{"id":1459412,"name":"Wendy Rosenthal","orcid":null,"position":3,"is_corresponding":false},{"id":420695,"name":"Sophie S. Jang","orcid":"0000-0002-8074-5058","position":4,"is_corresponding":false},{"id":927518,"name":"Yue Chen","orcid":"0000-0002-1011-2781","position":5,"is_corresponding":false},{"id":260360,"name":"Kevin M. Jude","orcid":"0000-0002-3675-5136","position":6,"is_corresponding":false},{"id":984474,"name":"Leon Su","orcid":"0000-0002-0318-6096","position":7,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":8,"is_corresponding":false},{"id":7899,"name":"Jeffrey A. Bluestone","orcid":"0000-0001-8793-7848","position":9,"is_corresponding":false},{"id":285543,"name":"Qizhi Tang","orcid":"0000-0001-7313-3574","position":10,"is_corresponding":false},{"id":563049,"name":"Alyssa Indart","orcid":"0000-0003-2662-0964","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40777342","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}