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Magnesium sensing via LFA-1 regulates CD8+ T cell effector function
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Authors
Lötscher, Jonas
Martí i Líndez, Adrià-Arnau
Kirchhammer, Nicole
Cribioli, Elisabetta
Giordano Attianese, Greta Maria Paola
Trefny, Marcel P.
Rothschild, Sacha I.
Strati, Paolo
Künzli, Marco
Lotter, Claudia
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Publisher
Elsevier
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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Keywords
immune control, memory CD8 T cells, microenvironment, Mg2+, co-stimulation/LFA-1, integration of microenvironment and T cell function, tumor-specific T cells, T cell engaging antibodies
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Citation
Lötscher, J., Martí i Líndez, A.-A., Kirchhammer, N., Cribioli, E., Giordano Attianese, G. M. P., Trefny, M. P., Rothschild, S. I., Strati, P., Künzli, M., Lotter, C., Schenk, S. H., Dehio, P., Löliger, J., Litzler, L., Schreiner, D., Koch, V., Page, N., Lee, D., Grählert, J., et al. (2022). Magnesium sensing via LFA-1 regulates CD8+ T cell effector function. Cell, 185(4), 585–602. https://doi.org/10.1016/j.cell.2021.12.039