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

Autor:	Lötscher J; Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Martí I Líndez AA; 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., Kirchhammer N; Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Cribioli E; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland., Giordano Attianese GMP; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland., Trefny MP; Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Lenz M; University of Applied Science Northwestern Switzerland, Institute for Ecopreneurship, 4132 Muttenz, Switzerland., Rothschild SI; Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland; Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland., Strati P; Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Künzli M; Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland., Lotter C; Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland., Schenk SH; Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland., Dehio P; Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Löliger J; Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Litzler L; Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland., Schreiner D; Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland., Koch V; Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Page N; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland., Lee D; Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Grählert J; Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Kuzmin D; Hornet Therapeutics Ltd, London SW1Y 5ES, UK; Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA., Burgener AV; Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland., Merkler D; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland., Pless M; Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland; Department of Oncology, Cantonal Hospital Winterthur, 8400 Winterthur, Switzerland., Balmer ML; 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., Reith W; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Huwyler J; Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland., Irving M; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland., King CG; Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland., Zippelius A; 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., Hess C; 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Feb 17; Vol. 185 (4), pp. 585-602.e29. Date of Electronic Publication: 2022 Jan 19.
DOI:	10.1016/j.cell.2021.12.039
Abstrakt:	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. Competing Interests: 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. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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