Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features
Abstract Natural Killer (NK) cells play pivotal immunological roles including direct cytotoxic effector function and secretion of inflammatory and immunomodulating cytokines. In the context of chronic inflammation, NK cell fitness decreases during disease progression through currently unknown mechan...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61196-0 |
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| author | Valentin Picant Lara Revol-Bauz Laurie Tonon Timothée Casini Aurélien Voissière Dominique Poujol Emilie Picard Céline Rodriguez Cyril Degletagne Emily Sible Uzma Hasan Anthony Ferrari Christophe Caux Nathalie Bendriss-Vermare |
| author_facet | Valentin Picant Lara Revol-Bauz Laurie Tonon Timothée Casini Aurélien Voissière Dominique Poujol Emilie Picard Céline Rodriguez Cyril Degletagne Emily Sible Uzma Hasan Anthony Ferrari Christophe Caux Nathalie Bendriss-Vermare |
| author_sort | Valentin Picant |
| collection | DOAJ |
| description | Abstract Natural Killer (NK) cells play pivotal immunological roles including direct cytotoxic effector function and secretion of inflammatory and immunomodulating cytokines. In the context of chronic inflammation, NK cell fitness decreases during disease progression through currently unknown mechanisms. Here, we demonstrate that Interleukin-35 (IL-35) inhibits human NK cell proliferation, pro-inflammatory, and cytotoxic functions, while promoting secretion of TGF-β and proangiogenic factors in vitro. We show prolonged exposure to IL-35 converts both conventional and adaptive NK cells into CD9+CD103+CD49a+ ILC1-like cells via autocrine TGF-β. We assess cancer patient-derived public datasets and reveal the presence of IL-35-producing cells and IL-35-receptor-expressing NK/ILC1-like cells within the tumor microenvironment and associate IL-35 with poor prognosis. Collectively, our findings identify and implicate IL-35 as a key driver of NK cell plasticity, promoting the acquisition of features associated with tissue residency and weakened effector functions, and could be relevant in pathophysiological contexts, highlighting IL-35 as an attractive target for future immunotherapies aimed at enhancing NK cell clinical activity. |
| format | Article |
| id | doaj-art-b99124fadba94e79b07d865d8330b397 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b99124fadba94e79b07d865d8330b3972025-08-20T04:01:35ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-61196-0Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency featuresValentin Picant0Lara Revol-Bauz1Laurie Tonon2Timothée Casini3Aurélien Voissière4Dominique Poujol5Emilie Picard6Céline Rodriguez7Cyril Degletagne8Emily Sible9Uzma Hasan10Anthony Ferrari11Christophe Caux12Nathalie Bendriss-Vermare13CISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardSynergie-Lyon-Cancer Fundation, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardGenomic platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCentre International de Recherche en Infectiologie, CIRI, INSERM U1111Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon BérardSynergie-Lyon-Cancer Fundation, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardCISTAR team, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon BérardAbstract Natural Killer (NK) cells play pivotal immunological roles including direct cytotoxic effector function and secretion of inflammatory and immunomodulating cytokines. In the context of chronic inflammation, NK cell fitness decreases during disease progression through currently unknown mechanisms. Here, we demonstrate that Interleukin-35 (IL-35) inhibits human NK cell proliferation, pro-inflammatory, and cytotoxic functions, while promoting secretion of TGF-β and proangiogenic factors in vitro. We show prolonged exposure to IL-35 converts both conventional and adaptive NK cells into CD9+CD103+CD49a+ ILC1-like cells via autocrine TGF-β. We assess cancer patient-derived public datasets and reveal the presence of IL-35-producing cells and IL-35-receptor-expressing NK/ILC1-like cells within the tumor microenvironment and associate IL-35 with poor prognosis. Collectively, our findings identify and implicate IL-35 as a key driver of NK cell plasticity, promoting the acquisition of features associated with tissue residency and weakened effector functions, and could be relevant in pathophysiological contexts, highlighting IL-35 as an attractive target for future immunotherapies aimed at enhancing NK cell clinical activity.https://doi.org/10.1038/s41467-025-61196-0 |
| spellingShingle | Valentin Picant Lara Revol-Bauz Laurie Tonon Timothée Casini Aurélien Voissière Dominique Poujol Emilie Picard Céline Rodriguez Cyril Degletagne Emily Sible Uzma Hasan Anthony Ferrari Christophe Caux Nathalie Bendriss-Vermare Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features Nature Communications |
| title | Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features |
| title_full | Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features |
| title_fullStr | Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features |
| title_full_unstemmed | Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features |
| title_short | Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features |
| title_sort | interleukin 35 impairs human nk cell effector functions and induces their ilc1 like conversion with tissue residency features |
| url | https://doi.org/10.1038/s41467-025-61196-0 |
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