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Updated: Oct 6, 2025
Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
Magnesium sensing via LFA-1 regulates CD8+ T cell effector function
Jonas Lötscher1, Adrià-Arnau Martí I Líndez2, Nicole Kirchhammer3
1Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland.
Insights
Magnesium is crucial for T-cell immunity. This study reveals magnesium enables the LFA-1 molecule to activate T-cells, enhancing their ability to fight pathogens and tumors, and improving cancer therapies.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- The role of extracellular magnesium in cellular immunity is not well understood.
- Magnesium is an essential mineral involved in numerous biological processes.
Purpose of the Study:
- To investigate the function of extracellular magnesium in T-cell activation and anti-tumor immunity.
- To explore the mechanism by which magnesium influences T-cell co-stimulation via LFA-1.
Main Methods:
- Investigated the effect of magnesium on LFA-1 conformation and function on CD8+ T-cells.
- Assessed T-cell signaling, metabolism, and cytotoxicity in varying magnesium conditions.
- Analyzed clinical data from patients treated with CAR T-cells and immune checkpoint antibodies.
Main Results:
- Magnesium is required for the active conformation of LFA-1 on T-cells, enhancing calcium flux, signal transduction, and cytotoxicity.
- Magnesium sufficiency improved T-cell performance against pathogens and tumors, and enhanced CAR T-cell and bispecific antibody efficacy.
- Low serum magnesium levels correlated with poorer outcomes in patients undergoing immunotherapy.
Conclusions:
- The magnesium-LFA-1 axis is a critical link between nutrient sensing and T-cell co-stimulation.
- Magnesium levels directly impact T-cell function and therapeutic outcomes in cancer immunotherapy.
- Targeting the magnesium-LFA-1 interaction represents a potential therapeutic strategy to enhance anti-cancer immunity.
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.
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