IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis in healthy participants
5 affiliations
- 1Immune Tolerance Network, University of Michigan, Ann Arbor, Michigan, USA.
- 2Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
- 3Merck & Co., Inc., Rahway, New Jersey, USA.
- 4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA.
- 5Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
Abstract
Tregs play an essential role in immune tolerance, and Treg-promoting therapies are in development for the treatment of many inflammatory disorders. IL-2–based 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–dependent capture of CD80 and CD86 from non-Tregs. These results shed light onto underlying mechanisms by which Treg-targeted therapy may promote immune tolerance.
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BibTeX
@article{cooney2026mutein,
title = {{IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis in healthy participants}},
author = {Laura A. Cooney and Mitch Fahning and Liliane Khoryati and Anna Kus and Sheila Scheiding and Lori Blanchfield and Matt Lawrance and Basilin Benson and Kristina M. Harris and Gretchen A. Baltus and Shiuli Agarwal and Richard Wnek and Johannes F. Scheid and Kiki Cunningham-Bussel and Nancy D. Kim and S. Aubrey Stoch and Jyothsna Visweswaraiah and Nathan Higginson-Scott and Katalin Kis-Toth and Joanne L. Viney and Kevin L. Otipoby and Erik Sampson and Bridget Larkin and Daniel J. Campbell and S. Alice Long},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.193744},
url = {https://doi.org/10.1172/jci.insight.193744},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis in healthy participants
AU - Laura A. Cooney
AU - Mitch Fahning
AU - Liliane Khoryati
AU - Anna Kus
AU - Sheila Scheiding
AU - Lori Blanchfield
AU - Matt Lawrance
AU - Basilin Benson
AU - Kristina M. Harris
AU - Gretchen A. Baltus
AU - Shiuli Agarwal
AU - Richard Wnek
AU - Johannes F. Scheid
AU - Kiki Cunningham-Bussel
AU - Nancy D. Kim
AU - S. Aubrey Stoch
AU - Jyothsna Visweswaraiah
AU - Nathan Higginson-Scott
AU - Katalin Kis-Toth
AU - Joanne L. Viney
AU - Kevin L. Otipoby
AU - Erik Sampson
AU - Bridget Larkin
AU - Daniel J. Campbell
AU - S. Alice Long
PY - 2026
DA - 2026/09/17
JO - JCI Insight
DO - 10.1172/jci.insight.193744
UR - https://doi.org/10.1172/jci.insight.193744
AB - Tregs play an essential role in immune tolerance, and Treg-promoting therapies are in development for the treatment of many inflammatory disorders. IL-2–based 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–dependent capture of CD80 and CD86 from non-Tregs. These results shed light onto underlying mechanisms by which Treg-targeted therapy may promote immune tolerance.
SN - 2379-3708
ER -