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

Lötscher, Jonas; Martí I Líndez, Adrià-Arnau; Kirchhammer, Nicole; Cribioli, Elisabetta; Giordano, Greta; Trefny, Marcel P; Lenz, Markus; Rothschild, Sacha I; Strati, Paolo; Künzli, Marco; Lotter, Claudia; Schenk, Susanne H; Dehio, Philippe; Löliger, Jordan; Litzler, Ludivine; Schreiner, David; Koch, Victoria; Page, Nicolas; Lee, Dahye; Grählert, Jasmin; ... (2022). Magnesium sensing via LFA-1 regulates CD8+ T cell effector function. Cell, 185(4), 585-602.e29. Cell Press 10.1016/j.cell.2021.12.039

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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.

Item Type:

 Journal Article (Original Article)

Division/Institute:

 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Endokrinologie / Diabetologie (Erwachsene)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Endocrinology, Diabetology and Clinical Nutrition

UniBE Contributor:

 Balmer, Maria Luisa

Subjects:

 600 Technology > 610 Medicine & health

ISSN:

 0092-8674

Publisher:

 Cell Press

Language:

 English

Submitter:

 Laura Cavalli

Date Deposited:

 11 Feb 2022 11:43

Last Modified:

 05 Dec 2022 16:05

Publisher DOI:

 10.1016/j.cell.2021.12.039

PubMed ID:

 35051368

Uncontrolled 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

BORIS DOI:

URI:

 https://boris.unibe.ch/id/eprint/164827

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