Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells

Davide G. Franchina, Henry Kurniawan, Melanie Grusdat, Carole Binsfeld, Luana Guerra, Lynn Bonetti, Leticia Soriano-Baguet, Anouk Ewen, Takumi Kobayashi, Sophie Farinelle, Anna Rita Minafra, Niels Vandamme, Anaïs Carpentier, Felix K. Borgmann, Christian Jäger, Ying Chen, Markus Kleinewietfeld, Vasilis Vasiliou, Michel Mittelbronn, Karsten Hiller, Philipp A. Lang and Dirk Brenner ()
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Davide G. Franchina: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Henry Kurniawan: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Melanie Grusdat: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Carole Binsfeld: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Luana Guerra: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Lynn Bonetti: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Leticia Soriano-Baguet: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Anouk Ewen: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Takumi Kobayashi: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Sophie Farinelle: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Anna Rita Minafra: Heinrich-Heine-University
Niels Vandamme: National Data Mining and Modelling for Biomedicine, VIB Center for Inflammation Research
Anaïs Carpentier: National Center of Pathology (NCP), Laboratoire National de Santé (LNS)
Felix K. Borgmann: National Center of Pathology (NCP), Laboratoire National de Santé (LNS)
Christian Jäger: University of Luxembourg
Ying Chen: Department of Environmental Health Sciences, Yale School of Public Health
Markus Kleinewietfeld: VIB Center for Inflammation Research (IRC) Hasselt University
Vasilis Vasiliou: Department of Environmental Health Sciences, Yale School of Public Health
Michel Mittelbronn: National Center of Pathology (NCP), Laboratoire National de Santé (LNS)
Karsten Hiller: Technische Universität Braunschweig
Philipp A. Lang: Heinrich-Heine-University
Dirk Brenner: Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.

Date: 2022
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DOI: 10.1038/s41467-022-29426-x

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