作者
Jonas Lötscher,Adrià-Arnau Martí i Líndez,Nicole Kirchhammer,Elisabetta Cribioli,Greta Giordano,Marcel P. Trefny,Markus Lenz,Sacha I. Rothschild,Paolo Strati,Marco Künzli,Claudia Lotter,Susanne Schenk,Philippe Dehio,Jordan Löliger,Ludivine C. Litzler,David Schreiner,Victoria Koch,Nicolas Pagé,Dahye Lee,Jasmin Grählert,Dmitry Kuzmin,Anne‐Valérie Burgener,Doron Merkler,Miklos Pless,Maria L. Balmer,Walter Reith,Jörg Huwyler,Melita Irving,Catrina E. King,Alfred Zippelius,Christoph Hess
摘要
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.