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

Article Article scientifique Article Magnesium sensing via LFA-1 regulates CD8+ T cell effector function eng 2022-01-13 2022-02-17 author Lötscher Jonas author Marti Lindez Adria-Arnau 826235 author Kirchhammer Nicole author Cribioli Elisabetta author Giordano Greta author Trefny Marcel P author Lenz Markus author Rothschild Sacha I author Strati Paolo author Künzli Marco author Lotter Claudia author Schenk Susanne H author Dehio Philippe author Löliger Jordan author Litzler Ludivine author Schreiner David author Koch Victoria author Page Nicolas 796315 author Lee Dahye author Grählert Jasmin author Kuzmin Dmitry author Burgener Anne-Valérie author Merkler Doron 735735 author Pless Miklos author Balmer Maria L author Reith Walter 25482 author Huwyler Jörg author Irving Melita author King Carolyn G author Zippelius Alfred author Hess Christoph 585-602.e29 10.1016/j.cell.2021.12.039 35051368 0092-8674 https://www.sciencedirect.com/science/article/pii/S0092867421015610 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. CAR T cells Mg2+ T cell engaging antibodies Co-stimulation/LFA-1 Immune control Integration of microenvironment and T cell function Magnesium Memory CD8 T cells Microenvironment Tumor-specific T cells Dewey 616.07 Swiss National Science Foundation The role of free Magnesium as second messenger in T cell subpopulations 323530_171148 CH Careers;Academic and research careers (non-professorial);MD-PhD fellowships Swiss National Science Foundation Serine metabolism and T cell migration 323530_183980 CH Careers;Academic and research careers (non-professorial);MD-PhD fellowships Swiss National Science Foundation Reprogramming of acetate metabolism in CD8+ T cells during re-call responses PMPDP3_171261 CH Careers;Academic and research careers (non-professorial) Swiss National Science Foundation Immunometabolic sensing of bacterial metabolites driving diet-induced obesity PCEFP3_194618 CH Careers Novartis Foundation 17C141 Swiss National Science Foundation Genome-wide CRISPR screen to identify genes involved in T cell dysfunction and novel targets for cancer immunotherapy 320030_188576 CH Project funding Swiss National Science Foundation Role of glucose and serine metabolism in regulating the CD8+ T cell memory response 31003A_172848 CH Project funding Swiss National Science Foundation The role of the endoplasmic reticulum in regulating T cell (dys-)function 310030_192677 CH Project funding 137 Département de pathologie et immunologie 21F false 565 La Sclérose en plaques 908 221 Groupe Reith Walter (pathologie et immunologie) 282 Cell 185 4 82f62ceb-808a-4e18-8ca7-026973418737 Article (Published version) Restricted Magnesium sensing.pdf 7708164 application/pdf ca7642dd-a04b-4958-988e-78c5d3e12133 Appendix Restricted 1-s2.0-S0092867421015610-mmc1.pdf 47044 application/pdf Vignette Public 1-s2.0-S0092867421015610-fx1_lrg.jpg 297892 image/jpeg restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Marti Lindez, Adria-Arnau