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ResearchIn-Press PreviewClinical ResearchImmunology Open Access | 10.1172/jci.insight.193744

IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis activity in healthy participants

Laura A. Cooney,1 Mitch Fahning,2 Liliane Khoryati,2 Anna Kus,2 Sheila Scheiding,2 Lori Blanchfield,2 Matthew Lawrance,2 Basilin Benson,2 Kristina M. Harris,1 Gretchen A. Baltus,3 Shiuli Agarwal,3 Richard Wnek,3 Johannes F. Scheid,3 Kiki Cunningham-Bussel,3 Nancy D. Kim,3 S. Aubrey Stoch,3 Jyothsna Visweswaraiah,4 Nathan Higginson-Scott,4 Katalin Kis-Toth,4 Joanne L. Viney,4 Kevin L. Otipoby,4 Erik Sampson,4 Bridget Larkin,4 Daniel J. Campbell,2 and S. Alice Long2

1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

Find articles by Cunningham-Bussel, K. in: PubMed | Google Scholar

1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

Find articles by Kim, N. in: PubMed | Google Scholar

1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

Find articles by Stoch, S. in: PubMed | Google Scholar

1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

Find articles by Sampson, E. in: PubMed | Google Scholar

1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

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1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

Find articles by Campbell, D. in: PubMed | Google Scholar |

1Immune Tolerance Network, University of Michigan, Ann Arbor, United States of America

2Benaroya Research Institute at Virginia Mason, Seattle, United States of America

3Merck & Co., Inc., Rahway, United States of America

4Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, United States of America

Find articles by Long, S. in: PubMed | Google Scholar |

Published September 17, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.193744.
Copyright © 2026, Cooney et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 17, 2026 - Version history
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Abstract

Tregs play an essential role in immune tolerance, and Treg-promoting therapies are in development for the treatment of many inflammatory disorders. Interleukin-2 (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 pre-clinical studies. Following a single subcutaneous dose in humans, thymic-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 non-lymphoid tissue, as well as increased transendocytosis 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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