Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models
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 whil...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60082-z |
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| author | Janie Robert Manon Feuillolay María de Temple-Llavero Reginald Florian Akossi Vanessa Mhanna Mustapha Cheraï Gwladys Fourcade Frédéric Charlotte Nicolas Tchitchek Tian Mi Benjamin Youngblood Thomas Vazquez Michelle Rosenzwajg David Klatzmann |
| author_facet | Janie Robert Manon Feuillolay María de Temple-Llavero Reginald Florian Akossi Vanessa Mhanna Mustapha Cheraï Gwladys Fourcade Frédéric Charlotte Nicolas Tchitchek Tian Mi Benjamin Youngblood Thomas Vazquez Michelle Rosenzwajg David Klatzmann |
| author_sort | Janie Robert |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-32aca3a9a4844e81818c9aec6f7d562f |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-32aca3a9a4844e81818c9aec6f7d562f2025-08-20T03:22:07ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-60082-zExpression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune modelsJanie Robert0Manon Feuillolay1María de Temple-Llavero2Reginald Florian Akossi3Vanessa Mhanna4Mustapha Cheraï5Gwladys Fourcade6Frédéric Charlotte7Nicolas Tchitchek8Tian Mi9Benjamin Youngblood10Thomas Vazquez11Michelle Rosenzwajg12David Klatzmann13Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Assistance Publique - Hôpitaux de Paris, Clinical Investigation Center for Biotherapy and Immunology (CIC-BTi), Hôpital Pitié-SalpêtrièreSorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Assistance Publique - Hôpitaux de Paris, Pathology department, Hôpital Pitié-SalpêtrièreSorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Immunology, MS 351, St. Jude Children’s Research HospitalImmunology, MS 351, St. Jude Children’s Research HospitalILTOO Pharma, 10 rue des ReculettesSorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3)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.https://doi.org/10.1038/s41467-025-60082-z |
| spellingShingle | Janie Robert Manon Feuillolay María de Temple-Llavero Reginald Florian Akossi Vanessa Mhanna Mustapha Cheraï Gwladys Fourcade Frédéric Charlotte Nicolas Tchitchek Tian Mi Benjamin Youngblood Thomas Vazquez Michelle Rosenzwajg David Klatzmann Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models Nature Communications |
| title | Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models |
| title_full | Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models |
| title_fullStr | Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models |
| title_full_unstemmed | Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models |
| title_short | Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models |
| title_sort | expression of an interleukin 2 partial agonist enhances regulatory t cell persistence and efficacy in mouse autoimmune models |
| url | https://doi.org/10.1038/s41467-025-60082-z |
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