{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:02:24Z","timestamp":1790704944958,"version":"4.1.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Amgen","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"https:\/\/ror.org\/03g03ge92","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Low-dose interleukin-2 (IL-2) and IL-2 muteins are being developed to expand regulatory T cells (Tregs) for autoimmune disease therapy, but injection site reactions (ISRs) remain frequent and poorly understood. Here we show IL2Mut24, a murine surrogate of IL-2 receptor \u03b1 (IL-2R\u03b1, CD25)-biased IL-2 mutein, enhances Treg expansion yet paradoxically exacerbates cutaneous inflammation compared to wild-type IL-2. Using immunodeficient mice, antibody blockade and adoptive transfer, we identify group 2 innate lymphoid cells (ILC2s) as key drivers of IL-2-induced skin inflammation, defining a CD25-dependent innate activation axis that constrains immune tolerance. In cynomolgus monkeys, the CD25-biased IL-2 mutein efavaleukin alfa promotes greater peripheral Treg expansion than aldesleukin (recombinant human IL-2) but is accompanied by transient increases in IL-5 and dose-dependent ISRs, indicating conservation of this innate inflammatory program across species. To improve the therapeutic window, we engineer receptor clamps by linking IL2Mut24 to antibodies against CD25 to restrict IL-2 access to CD25. This receptor-tuned IL-2 preserves Treg selectivity, suppresses ISRs, and outperforms IL2Mut24 in experimental autoimmune encephalomyelitis by restraining Th17 responses. These findings reveal a conserved innate mechanism underlying IL-2\u2013associated toxicity and establish receptor-tuning as a strategy to improve the safety and efficacy of IL-2\u2013based immunotherapy.<\/jats:p>","DOI":"10.1172\/jci207126","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:50:08Z","timestamp":1790704208000},"source":"Crossref","is-referenced-by-count":0,"title":["Receptor-tuned Interleukin-2 Mutein Decouples Treg Expansion from ILC2-driven Cutaneous Inflammation"],"prefix":"10.1172","author":[{"given":"Anupama","family":"Sahoo","sequence":"first","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Moorman","sequence":"additional","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Tsenkova","sequence":"additional","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jing","sequence":"additional","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Valdovinos","sequence":"additional","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Luo","sequence":"additional","affiliation":[{"name":"Discovery Sciences, Advanced Technologies & AI, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiping","family":"Lu","sequence":"additional","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Discovery Protein Science, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee R.","family":"Hukkanen","sequence":"additional","affiliation":[{"name":"Translational Safety & Risk Sciences, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Fort","sequence":"additional","affiliation":[{"name":"Translational Safety & Risk Sciences, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen S.H.","family":"Tang","sequence":"additional","affiliation":[{"name":"Discovery Protein Science, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronya","family":"Primack","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shweta","family":"Mandavalli","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwen","family":"Deng","sequence":"additional","affiliation":[{"name":"Inflammation Research, Amgen Inc., South San Francisco, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,29]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/207126\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:50:09Z","timestamp":1790704209000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/207126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":0,"alternative-id":["10.1172\/JCI207126"],"URL":"https:\/\/doi.org\/10.1172\/jci207126","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}