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

Jonas Lötscher¹, Adrià-Arnau Martí I Líndez², Nicole Kirchhammer³, Elisabetta Cribioli⁴, Greta Maria Paola Giordano Attianese⁴, Marcel P Trefny³, Markus Lenz⁵, Sacha I Rothschild⁶, Paolo Strati⁷, Marco Künzli⁸, Claudia Lotter⁹, Susanne H Schenk⁹, Philippe Dehio¹, Jordan Löliger¹, Ludivine Litzler⁸, David Schreiner⁸, Victoria Koch³, Nicolas Page¹⁰, Dahye Lee¹, Jasmin Grählert¹, Dmitry Kuzmin¹¹, Anne-Valérie Burgener¹, Doron Merkler¹⁰, Miklos Pless¹², Maria L Balmer¹³, Walter Reith¹⁴, Jörg Huwyler⁹, Melita Irving⁴, Carolyn G King⁸, Alfred Zippelius¹⁵, Christoph Hess¹⁶

Affiliations

¹ Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland.
² Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
³ Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland.
⁴ Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
⁵ University of Applied Science Northwestern Switzerland, Institute for Ecopreneurship, 4132 Muttenz, Switzerland.
⁶ Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland; Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland.
⁷ Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland.
⁹ Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland.
¹⁰ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
¹¹ Hornet Therapeutics Ltd, London SW1Y 5ES, UK; Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA.
¹² Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland; Department of Oncology, Cantonal Hospital Winterthur, 8400 Winterthur, Switzerland.
¹³ Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department for Biomedical Research (DBMR), University Clinic for Diabetes, Endocrinology, Clinical Nutrition and Metabolism, Inselspital, University of Bern, 3008 Bern, Switzerland; Diabetes Center Berne (DCB), 3010 Bern, Switzerland.
¹⁴ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
¹⁵ Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland.
¹⁶ Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. Electronic address: chess@uhbs.ch.

PMID: 35051368
DOI: 10.1016/j.cell.2021.12.039

Free article

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

Jonas Lötscher et al. Cell. 2022.

Free article

. 2022 Feb 17;185(4):585-602.e29.

doi: 10.1016/j.cell.2021.12.039. Epub 2022 Jan 19.

Authors

Affiliations

¹ Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland.
² Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
³ Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland.
⁴ Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
⁵ University of Applied Science Northwestern Switzerland, Institute for Ecopreneurship, 4132 Muttenz, Switzerland.
⁶ Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland; Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland.
⁷ Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland.
⁹ Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland.
¹⁰ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
¹¹ Hornet Therapeutics Ltd, London SW1Y 5ES, UK; Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA.
¹² Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland; Department of Oncology, Cantonal Hospital Winterthur, 8400 Winterthur, Switzerland.
¹³ Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department for Biomedical Research (DBMR), University Clinic for Diabetes, Endocrinology, Clinical Nutrition and Metabolism, Inselspital, University of Bern, 3008 Bern, Switzerland; Diabetes Center Berne (DCB), 3010 Bern, Switzerland.
¹⁴ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
¹⁵ Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland.
¹⁶ Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. Electronic address: chess@uhbs.ch.

PMID: 35051368
DOI: 10.1016/j.cell.2021.12.039

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.

Keywords: CAR T cells; Mg2+; T cell engaging antibodies; co-stimulation/LFA-1; immune control; integration of microenvironment and T cell function; magnesium; memory CD8 T cells; microenvironment; tumor-specific T cells.

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Conflict of interest statement

Declaration of interests J. Lötscher and C.H. are inventors on a patent relating to this study filed by the University of Basel (EP20/191392.8), which is being developed by a start-up company (Hornet Therapeutics Ltd—Scientific Founder: C.H.). J.G. is an employee of Hornet Therapeutics. The authors declare no other competing financial interests.

Comment in

Magnesium: essential for T cells.
Bird L. Bird L. Nat Rev Immunol. 2022 Mar;22(3):144-145. doi: 10.1038/s41577-022-00688-2. Nat Rev Immunol. 2022. PMID: 35140365 No abstract available.
Magnesium for T cells: strong to the finish!
Vardhana S, Dustin ML. Vardhana S, et al. Trends Immunol. 2022 Apr;43(4):277-279. doi: 10.1016/j.it.2022.02.004. Epub 2022 Mar 5. Trends Immunol. 2022. PMID: 35260350

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

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Full Text Sources

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