Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models

Janie Robert, Manon Feuillolay, María Temple-Llavero, Reginald Florian Akossi, Vanessa Mhanna, Mustapha Cheraï, Gwladys Fourcade, Frédéric Charlotte, Nicolas Tchitchek, Tian Mi, Benjamin Youngblood, Thomas Vazquez, Michelle Rosenzwajg and David Klatzmann ()
Additional contact information
Janie Robert: Immunology-Immunopathology-Immunotherapy (i3)
Manon Feuillolay: Immunology-Immunopathology-Immunotherapy (i3)
María Temple-Llavero: Immunology-Immunopathology-Immunotherapy (i3)
Reginald Florian Akossi: Immunology-Immunopathology-Immunotherapy (i3)
Vanessa Mhanna: Immunology-Immunopathology-Immunotherapy (i3)
Mustapha Cheraï: Hôpital Pitié-Salpêtrière
Gwladys Fourcade: Immunology-Immunopathology-Immunotherapy (i3)
Frédéric Charlotte: Hôpital Pitié-Salpêtrière
Nicolas Tchitchek: Immunology-Immunopathology-Immunotherapy (i3)
Tian Mi: St. Jude Children’s Research Hospital
Benjamin Youngblood: St. Jude Children’s Research Hospital
Thomas Vazquez: 10 rue des Reculettes
Michelle Rosenzwajg: Immunology-Immunopathology-Immunotherapy (i3)
David Klatzmann: Immunology-Immunopathology-Immunotherapy (i3)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Regulatory T (Treg)-based cell therapy holds promise for autoimmune and inflammatory diseases, yet challenges remain regarding the functional stability and persistence of transferred Tregs. Here we engineer Tregs to express a partial agonist form of IL-2 (IL-2pa) to enhance persistence while avoiding toxicity from excessive signaling. Mouse Tregs expressing wild-type IL-2 (Tregs-IL2wt) have only a transient growth advantage, limited by toxicity from likely excessive signaling. By contrast, mouse Tregs-IL2pa exhibit sustained expansion, long-term survival in immunocompetent mice for over a year, and bystander expansion of endogenous Tregs. Tregs-IL2pa maintain a stable activated phenotype, Treg-specific demethylation, and a diverse TCR repertoire. In vivo, prophylactic transfer of Tregs-IL2pa ameliorates multi-organ autoimmunity in a Treg depletion-induced mouse autoimmune model. Lastly, compared with control Treg, human Tregs-IL2pa show enhanced survival in the IL-2-depleted environment of immune-deficient mice and improved control of xenogeneic graft-versus-host disease. Our results thus show that IL-2pa self-sufficiency enhances the stability, durability and efficacy of Treg therapies in preclinical settings.

Date: 2025
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DOI: 10.1038/s41467-025-60082-z

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