Magnesium sensing via LFA-1 regulates CD8+ T cell effector function, 2022, Jonas Lotscher et al

Highlights:

• LFA-1 mediated co-stimulation of CD8+ T cells depends on extracellular magnesium

• Magnesium is sensed via LFA-1 and regulates the effector function of CD8+ T cells

• Low serum magnesium levels are associated with worse outcomes in cancer immunotherapy

• The magnesium-LFA-1 axis has translational potential

Summary:

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.

https://www.sciencedirect.com/science/article/pii/S0092867421015610?dgcid=author