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Magnesium sensing via LFA-1 regulates CD8+ T cell effector function

Lötscher, Jonas and Marti Lindez, Adria-Arnau and Kirchhammer, Nicole and Cribioli, Elisabetta and Giordano, Greta and Trefny, Marcel P. and Lenz, Markus and Rothschild, Sacha I. and Strati, Paolo and Künzli, Marco and Lotter, Claudia and Schenk, Susanne H. and Dehio, Philippe and Löliger, Jordan and Litzler, Ludivine and Schreiner, David and Koch, Victoria and Page, Nicolas and Lee, Dahye and Grählert, Jasmin and Kuzmin, Dmitry and Burgener, Anne-Valérie and Merkler, Doron and Pless, Miklos and Balmer, Maria L. and Reith, Walter and Huwyler, Jörg and Irving, Melita and King, Carolyn G. and Zippelius, Alfred and Hess, Christoph. (2022) Magnesium sensing via LFA-1 regulates CD8+ T cell effector function. Cell, 185. pp. 1-18.

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Official URL: https://edoc.unibas.ch/87163/

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Abstract

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Onkologie > Medizinische Onkologie (Rochlitz)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Onkologie > Medizinische Onkologie (Rochlitz)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cancer Immunology and Biology (Zippelius/Rochlitz)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immune Cell Biology (King)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunobiology (Hess C)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
UniBasel Contributors:Huwyler, Jörg and Lötscher, Jonas and Marti Lindez, Adria-Arnau and Kirchhammer, Nicole and Trefny, Marcel and Künzli, Marco and Lotter, Claudia and Schenk, Susanne and Dehio, Philippe Georg and Löliger, Jordan Gabriel and Litzler, Ludivine and Schreiner, David and Koch, Victoria and Lee, Dahye and Grählert, Jasmin and Burgener, Anne Valérie and Balmer, Maria Luisa and King, Carolyn and Zippelius, Alfred and Hess, Christoph and Rothschild, Sacha
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:02 Feb 2022 19:15
Deposited On:02 Feb 2022 19:15

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