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IL-2\u2013based therapies increase Treg frequency, but little is known about impacts on Treg heterogeneity and function. We extended analyses of an IL-2 mutein (MK-6194) single ascending dose trial in healthy human participants by comprehensively defining Treg subsets and gene expression changes in vitro and in vivo. We found highly specific and dose-dependent activation and expansion of Tregs in clinical and preclinical studies. Following a single subcutaneous dose in humans, thymus-derived Tregs were selectively activated and expanded, while peripherally induced Tregs were unaffected. Expanded Tregs had increased expression of genes and proteins consistent with activation, suppressor function, and homing to nonlymphoid tissue, as well as increased transendocytotic activity, as measured by CTLA-4\u2013dependent capture of CD80 and CD86 from non-Tregs. These results shed light onto underlying mechanisms by which Treg-targeted therapy may promote immune tolerance.<\/jats:p>","DOI":"10.1172\/jci.insight.193744","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:00:38Z","timestamp":1789660838000},"source":"Crossref","is-referenced-by-count":0,"title":["IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis in healthy participants"],"prefix":"10.1172","volume":"11","author":[{"given":"Laura A.","family":"Cooney","sequence":"first","affiliation":[{"name":"Immune Tolerance Network, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitch","family":"Fahning","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliane","family":"Khoryati","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kus","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5466-9568","authenticated-orcid":true,"given":"Sheila","family":"Scheiding","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Blanchfield","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Lawrance","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basilin","family":"Benson","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6957-514X","authenticated-orcid":true,"given":"Kristina M.","family":"Harris","sequence":"additional","affiliation":[{"name":"Immune Tolerance Network, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen A.","family":"Baltus","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiuli","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wnek","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes F.","family":"Scheid","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiki","family":"Cunningham-Bussel","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy D.","family":"Kim","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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