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

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.

Automated summary

This study reveals the importance of extracellular magnesium in cellular immunity, particularly in the activation of the co-stimulatory molecule LFA-1. The findings demonstrate that magnesium-sufficiency enhances the function of immune cells and the effectiveness of T cell therapies. Low serum magnesium levels are associated with disease progression and reduced overall survival in patients receiving CAR T cell and immune checkpoint antibody treatments.