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

• DOI: 10.1016/j.cell.2021.12.039
• Publication Date: 2022-01-19T16:07:38Z
• Authors: Jonas Lötscher; Adrià-Arnau Martí...; Nicole Kirchhammer; Elisabetta Cribioli; Greta Maria Paola...; Marcel P. Trefny; Markus Lenz; Sacha I. Rothschild; Paolo Strati; Marco Künzli; Claudia Lotter; Susanne H. Schenk; Philippe Dehio; Jordan Löliger; Ludivine Litzler; David Schreiner; Victoria Koch; Nicolas Page; Dahye Lee; Jasmin Grählert; Dmitry Kuzmin; Anne-Valérie Burg...; Doron Merkler; Miklos Pless; Maria L. Balmer; Walter Reith; Jörg Huwyler; Melita Irving; Carolyn G. King; Alfred Zippelius; Christoph Hess
• Keywords: Immunological synapse; Reprogramming

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.