Glutathione is critical for NK cell-mediated immunity
Natural killer (NK) cells are essential for immune protection against tumors and viruses. Disease environments impose oxidative stress and impair immune cell functions. Glutathione (GSH) is a major cellular antioxidant and is critical for the immune response, but how it modulates NK cell function remains largely unknown. Using a mouse model with a specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) in NK cells, we demonstrate that GSH supports interleukin-15 (IL-15)-driven activation of NK cells. Gclc deficiency causes an intracellular accumulation of reactive oxygen species (ROS), which impairs the metabolism of NK cells. This is accompanied by defective proliferation and cytokine production concurrent with subverted mTOR and STAT5 activation. During acute lymphocytic choriomeningitis virus (LCMV) infection, Gclc-deficient NK cells are unable to suppress the antiviral T cell response. Remarkably, Gclc deficiency impairs NK cell-mediated protection against tumor lung metastases. Our findings highlight an essential role of GSH in maintaining NK cell functionality.
Authors
- Philipp A. Lang (ORCID: https://orcid.org/0000-0001-5341-0407)
- Lynn Bonetti
- Éric Vivier (ORCID: https://orcid.org/0000-0001-7022-8287)
- Carole Binsfeld
- Charlène Verschueren
- Joseph Longworth (ORCID: https://orcid.org/0000-0003-4644-921X)
- Toru Kobayashi (ORCID: https://orcid.org/0009-0004-6986-4437)
- Melanie Grusdat (ORCID: https://orcid.org/0000-0003-0708-0077)
- Davide G. Franchina (ORCID: https://orcid.org/0000-0001-9824-5302)
- Luana Guerra (ORCID: https://orcid.org/0000-0003-4863-9244)
- Henry Kurniawan (ORCID: https://orcid.org/0000-0001-5925-6893)
- Vasilis Vasiliou (ORCID: https://orcid.org/0000-0003-2552-3118)
- Sophie Farinelle
- Catherine Dostert
- Georgios Theodorakis
- Dirk Brenner
- Leticia Soriano-Baguet
- Sarah Alhamouieh
- Ying Chen
- Anouk Ewen
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Luxembourg (LU)
- Université Paris-Saclay (FR)
- Luxembourg Institute of Health (LU)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Hôpital de la Timone (FR)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-02-23
- DOI
- https://doi.org/10.1016/j.celrep.2026.116986
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Aix-Marseille Université
- Université du Luxembourg
- European Commission
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Institut National de la Santé et de la Recherche Médicale
- Bundesministerium für Bildung und Forschung
- Fonds De La Recherche Scientifique - FNRS
- Centre National de la Recherche Scientifique
- Canceropôle PACA
- Institut National Du Cancer
- Institut Gustave-Roussy
- Fondation Gustave Roussy
- RIKEN