Lötscher, JonasMartí i Líndez, Adrià-ArnauKirchhammer, NicoleCribioli, ElisabettaGiordano Attianese, Greta Maria PaolaTrefny, Marcel P.Rothschild, Sacha I.Strati, PaoloKünzli, MarcoLotter, ClaudiaSchenk, Susanne H.Dehio, PhilippeLöliger, JordanLitzler, LudivineSchreiner, DavidKoch, VictoriaPage, NicolasLee, DahyeGrählert, JasminKuzmin, DmitryBurgener, Anne-ValérieMerkler, DoronPless, MiklosBalmer, Maria L.Reith, WalterHuwyler, JörgIrving, MelitaKing, Carolyn G.Zippelius, AlfredHess, ChristophLenz, Markus2023-04-032022-10-122023-04-0320220092-86741097-417210.1016/j.cell.2021.12.039https://irf.fhnw.ch/handle/11654/33940https://doi.org/10.26041/fhnw-4770The 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.enT cell engaging antibodiesImmune controlMemory CD8 T cellsMicroenvironmentCo-stimulation/LFA-1Integration of microenvironment and T cell functionTumor-specific T cells500 - Naturwissenschaften01A - Beitrag in wissenschaftlicher Zeitschrift585-602.e29